User login
Take action to mitigate CVD risk in RA patients
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Targeted triplet shows potential for B-cell cancers
A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.
The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.
“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”
The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.
A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.
In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.
In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.
Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.
Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.
The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).
Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.
“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”
The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.
SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.
A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.
The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.
“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”
The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.
A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.
In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.
In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.
Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.
Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.
The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).
Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.
“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”
The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.
SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.
A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.
The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.
“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”
The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.
A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.
In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.
In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.
Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.
Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.
The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).
Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.
“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”
The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.
SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.
FROM LANCET HAEMATOLOGY
Key clinical point:
Major finding: Out of 44 patients, 37 (84%) achieved a partial or complete response to therapy.
Study details: A phase 1, multicenter, dose-escalation and dose-expansion trial involving 46 patients with chronic lymphocytic leukemia, small lymphocytic leukemia, or relapsed/refractory non-Hodgkin lymphoma.
Disclosures: The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.
Source: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.
Adolescents’ screen time tied to more depression, less sleep
Screen-based activities and sleep behaviors could be “intervention targets” for adolescents with depressive symptoms, results of a study of almost 3,000 U.S. adolescents suggest.
“Overall, our results indicated that [social messaging, Web surfing, TV/movie watching, and video gaming] ... were associated with greater depressive symptoms and poorer sleep characteristics,” Xian Li, PhD, and her associates reported in Sleep Medicine.
Numerous studies previously have demonstrated a positive link between adolescent depression and exposure to electronic devices, although little is known about the precise mechanism(s) of action involved and to what extent sleep plays a role. To address those gaps, Dr. Li, of the State University of New York at Stony Brook, and her associates examined four types of screen activities to determine whether symptoms of adolescent depression, sleep duration, and symptoms of insomnia – including problems falling asleep and staying asleep – are influenced in any way by those activities.
Using data from the Fragile Families and Child Wellbeing Study, a longitudinal urban birth cohort study that included an “oversampling of nonmarital births,” Dr. Li and her associates evaluated a total of 2,865 adolescents (mean 15.53 years of age; 48.2% female) self-identifying as African American (47.4%), Hispanic/Latino (23.7%), white (16.8%), or other/multiracial (12.1%). In participant interviews conducted with adolescents and caregivers during 2014-2016, 17.5% of caregivers reported having less than a high school education; 31.1% of teens lived in households below 100% of poverty; 32.8% came from single-mother families; and just 26.9% lived with both biological parents. The investigators assessed depressive symptoms at age 15 years by using five items from Center for Epidemiologic Studies Depression Scale.
Overall, Dr. Li and her associates found greater depressive symptoms associated with all four of the screen-based activities (P less than .01). In addition, more problems were observed with falling and staying asleep as well as shortened duration of sleep during the week for each of the activities monitored.
Social messaging, Web surfing, and time spent watching TV and movies appeared to be directly correlated with sleep characteristics, but the same could not be said for gaming, which showed only partial correlation with sleep characteristics. In that case, the authors speculated that the association between gaming and depression could be at least partly explained by individual characteristics such as trait neuroticism and self-control or a self-selection behavior in which those exhibiting greater signs of depression turn to gaming as an escape. “Thus, ,” Dr. Li and her associates wrote. The authors also noted a significant link between depressive symptoms at age 9 years and gaming behavior at age 15 years.
Several study limitations were noted. Causality and temporality could not be teased apart given that screen activities, sleep, and depressive symptoms all were measured concurrently at age 15 years. Screen activities also were noted to have captured only duration and not content or interactivity of the activities. Self-reports of screen time also might have been inaccurate because of general error in recall or even overlap in cases where participants were using more than one device simultaneously.
It is important to consider that while the relationships in the models might have statistical significance, “the effect size in the study as a whole are small.”
Nevertheless, they wrote, their findings “suggest that screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”
Future studies should examine the “temporal sequencing” of those three limitations as well as adding more informants, including parent and teacher reports, and methods for objectively measuring screen activities and sleep, the authors cautioned.
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor in chief of the journal Sleep Health.
SOURCE: Li X et al. Sleep Med. 2019 Feb 2. doi: 10.1016/j.sleep.2019.01.029.
Screen-based activities and sleep behaviors could be “intervention targets” for adolescents with depressive symptoms, results of a study of almost 3,000 U.S. adolescents suggest.
“Overall, our results indicated that [social messaging, Web surfing, TV/movie watching, and video gaming] ... were associated with greater depressive symptoms and poorer sleep characteristics,” Xian Li, PhD, and her associates reported in Sleep Medicine.
Numerous studies previously have demonstrated a positive link between adolescent depression and exposure to electronic devices, although little is known about the precise mechanism(s) of action involved and to what extent sleep plays a role. To address those gaps, Dr. Li, of the State University of New York at Stony Brook, and her associates examined four types of screen activities to determine whether symptoms of adolescent depression, sleep duration, and symptoms of insomnia – including problems falling asleep and staying asleep – are influenced in any way by those activities.
Using data from the Fragile Families and Child Wellbeing Study, a longitudinal urban birth cohort study that included an “oversampling of nonmarital births,” Dr. Li and her associates evaluated a total of 2,865 adolescents (mean 15.53 years of age; 48.2% female) self-identifying as African American (47.4%), Hispanic/Latino (23.7%), white (16.8%), or other/multiracial (12.1%). In participant interviews conducted with adolescents and caregivers during 2014-2016, 17.5% of caregivers reported having less than a high school education; 31.1% of teens lived in households below 100% of poverty; 32.8% came from single-mother families; and just 26.9% lived with both biological parents. The investigators assessed depressive symptoms at age 15 years by using five items from Center for Epidemiologic Studies Depression Scale.
Overall, Dr. Li and her associates found greater depressive symptoms associated with all four of the screen-based activities (P less than .01). In addition, more problems were observed with falling and staying asleep as well as shortened duration of sleep during the week for each of the activities monitored.
Social messaging, Web surfing, and time spent watching TV and movies appeared to be directly correlated with sleep characteristics, but the same could not be said for gaming, which showed only partial correlation with sleep characteristics. In that case, the authors speculated that the association between gaming and depression could be at least partly explained by individual characteristics such as trait neuroticism and self-control or a self-selection behavior in which those exhibiting greater signs of depression turn to gaming as an escape. “Thus, ,” Dr. Li and her associates wrote. The authors also noted a significant link between depressive symptoms at age 9 years and gaming behavior at age 15 years.
Several study limitations were noted. Causality and temporality could not be teased apart given that screen activities, sleep, and depressive symptoms all were measured concurrently at age 15 years. Screen activities also were noted to have captured only duration and not content or interactivity of the activities. Self-reports of screen time also might have been inaccurate because of general error in recall or even overlap in cases where participants were using more than one device simultaneously.
It is important to consider that while the relationships in the models might have statistical significance, “the effect size in the study as a whole are small.”
Nevertheless, they wrote, their findings “suggest that screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”
Future studies should examine the “temporal sequencing” of those three limitations as well as adding more informants, including parent and teacher reports, and methods for objectively measuring screen activities and sleep, the authors cautioned.
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor in chief of the journal Sleep Health.
SOURCE: Li X et al. Sleep Med. 2019 Feb 2. doi: 10.1016/j.sleep.2019.01.029.
Screen-based activities and sleep behaviors could be “intervention targets” for adolescents with depressive symptoms, results of a study of almost 3,000 U.S. adolescents suggest.
“Overall, our results indicated that [social messaging, Web surfing, TV/movie watching, and video gaming] ... were associated with greater depressive symptoms and poorer sleep characteristics,” Xian Li, PhD, and her associates reported in Sleep Medicine.
Numerous studies previously have demonstrated a positive link between adolescent depression and exposure to electronic devices, although little is known about the precise mechanism(s) of action involved and to what extent sleep plays a role. To address those gaps, Dr. Li, of the State University of New York at Stony Brook, and her associates examined four types of screen activities to determine whether symptoms of adolescent depression, sleep duration, and symptoms of insomnia – including problems falling asleep and staying asleep – are influenced in any way by those activities.
Using data from the Fragile Families and Child Wellbeing Study, a longitudinal urban birth cohort study that included an “oversampling of nonmarital births,” Dr. Li and her associates evaluated a total of 2,865 adolescents (mean 15.53 years of age; 48.2% female) self-identifying as African American (47.4%), Hispanic/Latino (23.7%), white (16.8%), or other/multiracial (12.1%). In participant interviews conducted with adolescents and caregivers during 2014-2016, 17.5% of caregivers reported having less than a high school education; 31.1% of teens lived in households below 100% of poverty; 32.8% came from single-mother families; and just 26.9% lived with both biological parents. The investigators assessed depressive symptoms at age 15 years by using five items from Center for Epidemiologic Studies Depression Scale.
Overall, Dr. Li and her associates found greater depressive symptoms associated with all four of the screen-based activities (P less than .01). In addition, more problems were observed with falling and staying asleep as well as shortened duration of sleep during the week for each of the activities monitored.
Social messaging, Web surfing, and time spent watching TV and movies appeared to be directly correlated with sleep characteristics, but the same could not be said for gaming, which showed only partial correlation with sleep characteristics. In that case, the authors speculated that the association between gaming and depression could be at least partly explained by individual characteristics such as trait neuroticism and self-control or a self-selection behavior in which those exhibiting greater signs of depression turn to gaming as an escape. “Thus, ,” Dr. Li and her associates wrote. The authors also noted a significant link between depressive symptoms at age 9 years and gaming behavior at age 15 years.
Several study limitations were noted. Causality and temporality could not be teased apart given that screen activities, sleep, and depressive symptoms all were measured concurrently at age 15 years. Screen activities also were noted to have captured only duration and not content or interactivity of the activities. Self-reports of screen time also might have been inaccurate because of general error in recall or even overlap in cases where participants were using more than one device simultaneously.
It is important to consider that while the relationships in the models might have statistical significance, “the effect size in the study as a whole are small.”
Nevertheless, they wrote, their findings “suggest that screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”
Future studies should examine the “temporal sequencing” of those three limitations as well as adding more informants, including parent and teacher reports, and methods for objectively measuring screen activities and sleep, the authors cautioned.
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor in chief of the journal Sleep Health.
SOURCE: Li X et al. Sleep Med. 2019 Feb 2. doi: 10.1016/j.sleep.2019.01.029.
FROM SLEEP MEDICINE
Key clinical point: “Screen-based activities have negative implications for both sleep quality and sleep quantity, which further relates to depressive symptoms.”
Major finding: Greater depressive symptoms were associated with all four of the screen-based activities (P less than .01).
Study details: Analysis of surveys from 2,865 U.S. adolescents who were asked about sleep duration and quality, typical daily screen time, and depressive symptoms.
Disclosures: The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and several private foundations. Dr. Buxton received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies. Dr. Hale received an honorarium from the National Sleep Foundation for her role as editor-in-chief of the journal Sleep Health.
Source: Li X et al. Sleep Med. 2019 Feb. 2. doi: 10.1016/j.sleep.2019.01.029.
Opioids often prescribed in low-income areas
Also today, undervaccination poses a particular danger to patients with HIV, patients with inflammatory bowl disease aren’t getting appropriate reproductive counseling, and the type of exercise does matter when it comes to preventing falls among elderly patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, undervaccination poses a particular danger to patients with HIV, patients with inflammatory bowl disease aren’t getting appropriate reproductive counseling, and the type of exercise does matter when it comes to preventing falls among elderly patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, undervaccination poses a particular danger to patients with HIV, patients with inflammatory bowl disease aren’t getting appropriate reproductive counseling, and the type of exercise does matter when it comes to preventing falls among elderly patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Chronic Myeloid Leukemia: A Review of TKI Therapy
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.
CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.
The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed.
Case Presentation
A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 103/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.
- What factors must be considered when selecting first-line therapy for this patient?
Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.
Imatinib
The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.1
The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.2 The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.3 The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.
Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.4
The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.5
Toxicity
Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.6 In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.7
Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.7
Dasatinib
Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.
Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.8
Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).9 Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.
Toxicity
Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.
During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.9 Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.7 Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).9 Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.10
Nilotinib
The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.11
Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.12 Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).12 Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.13 In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.13
Toxicity
Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.12 Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.12
More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.12
Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.7
If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.
Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.7
Bosutinib
Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.14
Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.15 These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.
Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).16
A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.17
Toxicity
On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.17
Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.17
If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.7
Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.7
Ponatinib
The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.18 The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.18 The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.19
Toxicity
In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.19 Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.19
Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.7
In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.7
In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.7
Case Conclusion
Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.
After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR.
Conclusion
With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML.
1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.
2. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
3. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917-927.
4. Baccarani M, Druker BJ, Branford S, et al. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol. 2014;99:616-624.
5. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125:915-923.
6. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
7. Radich JP, Deininger M, Abboud CN, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:1108-1135.
8. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91:869-874.
9. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients trial. J Clin Oncol. 2016;34:2333-3340.
10. Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114:261-263.
11. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27:107-112.
12. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.
13. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044-1054.
14. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91:1206-1214.
15. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica. 2018;103:1298-1307.
16. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486-3492.
17. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231-237.
18. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783-1796.
19. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.
CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.
The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed.
Case Presentation
A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 103/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.
- What factors must be considered when selecting first-line therapy for this patient?
Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.
Imatinib
The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.1
The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.2 The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.3 The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.
Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.4
The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.5
Toxicity
Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.6 In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.7
Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.7
Dasatinib
Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.
Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.8
Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).9 Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.
Toxicity
Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.
During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.9 Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.7 Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).9 Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.10
Nilotinib
The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.11
Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.12 Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).12 Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.13 In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.13
Toxicity
Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.12 Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.12
More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.12
Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.7
If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.
Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.7
Bosutinib
Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.14
Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.15 These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.
Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).16
A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.17
Toxicity
On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.17
Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.17
If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.7
Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.7
Ponatinib
The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.18 The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.18 The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.19
Toxicity
In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.19 Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.19
Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.7
In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.7
In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.7
Case Conclusion
Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.
After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR.
Conclusion
With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.
CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.
The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed.
Case Presentation
A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 103/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.
- What factors must be considered when selecting first-line therapy for this patient?
Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.
Imatinib
The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.1
The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.2 The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.3 The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.
Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.4
The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.5
Toxicity
Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.6 In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.7
Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.7
Dasatinib
Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.
Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.8
Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).9 Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.
Toxicity
Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.
During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.9 Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.7 Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).9 Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.10
Nilotinib
The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.11
Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.12 Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).12 Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.13 In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.13
Toxicity
Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.12 Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.12
More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.12
Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.7
If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.
Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.7
Bosutinib
Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.14
Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.15 These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.
Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).16
A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.17
Toxicity
On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.17
Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.17
If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.7
Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.7
Ponatinib
The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.18 The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.18 The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.19
Toxicity
In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.19 Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.19
Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.7
In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.7
In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.7
Case Conclusion
Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.
After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR.
Conclusion
With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML.
1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.
2. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
3. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917-927.
4. Baccarani M, Druker BJ, Branford S, et al. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol. 2014;99:616-624.
5. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125:915-923.
6. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
7. Radich JP, Deininger M, Abboud CN, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:1108-1135.
8. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91:869-874.
9. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients trial. J Clin Oncol. 2016;34:2333-3340.
10. Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114:261-263.
11. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27:107-112.
12. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.
13. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044-1054.
14. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91:1206-1214.
15. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica. 2018;103:1298-1307.
16. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486-3492.
17. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231-237.
18. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783-1796.
19. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404.
1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.
2. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
3. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917-927.
4. Baccarani M, Druker BJ, Branford S, et al. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol. 2014;99:616-624.
5. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125:915-923.
6. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
7. Radich JP, Deininger M, Abboud CN, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:1108-1135.
8. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91:869-874.
9. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients trial. J Clin Oncol. 2016;34:2333-3340.
10. Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114:261-263.
11. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27:107-112.
12. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.
13. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044-1054.
14. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91:1206-1214.
15. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica. 2018;103:1298-1307.
16. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486-3492.
17. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231-237.
18. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783-1796.
19. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404.
Irregular macule on back
The FP suspected that this could be a melanoma and took out his dermatoscope. (See “Dermoscopy in family medicine: A primer.”) The FP was initially concerned about melanoma because the lesion appeared chaotic, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the macule was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was >6 mm, but the history was insufficient to say whether it was Enlarging. Of course, 4 out of 5 positive criteria requires a tissue diagnosis.
Dermoscopy added evidence for regression in the center and an atypical network in the brown and black areas. The FP performed a deep shave biopsy (saucerization) with 2 mm margins to provide full sampling for the pathologist. (See the Watch & Learn video on “Shave biopsy.”) The depth of the tissue biopsy was approximately 1 to 1.5 mm, which was adequate for a lesion of this type. The pathology report confirmed melanoma in situ.
On a return visit, the FP performed a local wide excision with 5 mm margins down to the deep fat. The surgical specimen revealed only the scar at the biopsy site with no remaining cancer. This reassured the patient because it should provide a cure very near 100%. The FP provided counseling about sun protection and the need for regular skin exams.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1112-1123.
To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/
You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com
The FP suspected that this could be a melanoma and took out his dermatoscope. (See “Dermoscopy in family medicine: A primer.”) The FP was initially concerned about melanoma because the lesion appeared chaotic, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the macule was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was >6 mm, but the history was insufficient to say whether it was Enlarging. Of course, 4 out of 5 positive criteria requires a tissue diagnosis.
Dermoscopy added evidence for regression in the center and an atypical network in the brown and black areas. The FP performed a deep shave biopsy (saucerization) with 2 mm margins to provide full sampling for the pathologist. (See the Watch & Learn video on “Shave biopsy.”) The depth of the tissue biopsy was approximately 1 to 1.5 mm, which was adequate for a lesion of this type. The pathology report confirmed melanoma in situ.
On a return visit, the FP performed a local wide excision with 5 mm margins down to the deep fat. The surgical specimen revealed only the scar at the biopsy site with no remaining cancer. This reassured the patient because it should provide a cure very near 100%. The FP provided counseling about sun protection and the need for regular skin exams.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1112-1123.
To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/
You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com
The FP suspected that this could be a melanoma and took out his dermatoscope. (See “Dermoscopy in family medicine: A primer.”) The FP was initially concerned about melanoma because the lesion appeared chaotic, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the macule was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was >6 mm, but the history was insufficient to say whether it was Enlarging. Of course, 4 out of 5 positive criteria requires a tissue diagnosis.
Dermoscopy added evidence for regression in the center and an atypical network in the brown and black areas. The FP performed a deep shave biopsy (saucerization) with 2 mm margins to provide full sampling for the pathologist. (See the Watch & Learn video on “Shave biopsy.”) The depth of the tissue biopsy was approximately 1 to 1.5 mm, which was adequate for a lesion of this type. The pathology report confirmed melanoma in situ.
On a return visit, the FP performed a local wide excision with 5 mm margins down to the deep fat. The surgical specimen revealed only the scar at the biopsy site with no remaining cancer. This reassured the patient because it should provide a cure very near 100%. The FP provided counseling about sun protection and the need for regular skin exams.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1112-1123.
To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/
You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com
Love hormone plein air, posh preused Kleenex, and dieting plague vectors
Paint me like one of your French girls
If you’re trying to think of a fun Valentine’s activity, look no further than paint night! Normally associated with a ladies night out (and heavy on the wine), a recent study found that painting releases high levels of the “love hormone”, a.k.a. oxytocin, in men.
Researchers compared the levels of oxytocin with partners painting and partners playing board games, and were surprised by the results: While all the couples released oxytocin during these activities, men in paint class had the highest levels – twice as much as any other group.
Feel free to cite this study next time your man complains about being dragged to a paint-and-sip. Painting partners also experienced more touching than the gaming group (unless you count throwing Monopoly pieces at your significant other as touching).
You won’t get me sick, I’ll get me sick!
There are certain items that, after being used once, you really wouldn’t want to reuse. A snotty, mucus-filled tissue is pretty high up on that list ... or so you would hope. But that’s not thinking with real American entrepreneurial spirit! Welcome to Vaev Tissue, a startup based in Los Angeles that sells used tissues containing germs from a sick person for the bargain price of $79.99.
Yes, you read that correctly. They sell an $80 used tissue. The purpose, according to Vaev’s mission statement, is “to get sick on your own terms,” as “using a tissue that carries a human sneeze is safer than needles or pills.”
As you might expect, the tissues are popular with young parents and adults who are “critical” of vaccines. Who else could hear advice from actual doctors who told Time magazine that “there is nothing positive that can come from this, only things that are adverse,” or that the tissues are an “incredible liability,” and continue on, regardless?
And if you’re thinking, “If these people want to get sick, why not just have someone sneeze on them?” Don’t be ridiculous. Focus testers responded highly negatively to simply being handed a dirty tissue. The premium packaging and high price tag are a necessity.
Our advice? Well, as tempting as all this sounds, we think we’ll stick with washing our hands and not sticking used tissues in our faces. You know, like reasonable people.
Why Bullwinkle thinks pink
Flying squirrels are secretly doing their best flamingo impression – who knew? A forestry professor discovered, by happy accident, that flying squirrels are fluorescent – they glow hot pink under ultraviolet light.
Turns out, almost all species of gliders – even blue-helmeted Rocket “Rocky” J. Squirrel – are members of the Pink Ladies. They are one of the very few glowing mammals; the only other known mammalian species to have fluorescent fur are certain opossums.
But why do these airborne rodents glow pink? Is it because of an overintake of bubblegum? Are flying squirrels just really flamboyant but also shy? Are they huge fans of the singer Pink?
A biologist involved in studying these colorful critters hypothesized that the reason is slightly more related to environment than musical preference. Flying squirrels are nocturnal, making them most active when UV light is most prominent. The garish glow might have something to do with nighttime perception.
However, we don’t know the answer for sure. And in the meantime, we can choose to believe flying squirrels eat way too much cotton candy.
Buzz, feed, diet. Repeat
Guns don’t hurt this mass murderer. Police can’t arrest it. Background checks are pointless. A border wall won’t keep it out. So, how do you stop a mosquito?
Diet drugs.
Because female mosquitoes transmit malaria, Zika, and other diseases when they move from person to person feeding on human blood, investigators sought to curb that appetite by chemically re-creating the feeling of fullness they get after a big meal.
The lady killers in their study – Aedes aegypti, to be exact – when given an antiobesity drug that suppresses human appetite by activating neuropeptide receptors that regulate food intake, turned away from a tempting piece of nylon stocking that had been worn by one of the researchers. Further work showed that treated mosquitoes were as disinterested in feeding on a live mouse as mosquitoes that had already enjoyed a full blood meal.
The LOTME research staff (What? Of course, we have a research staff. You don’t?) is working on the mosquito problem too, although we’ve taken a somewhat different approach: The “volunteers” who walk into the mosquito-filled room wear a sign that says, “My blood will make your butt look bigger.”
Paint me like one of your French girls
If you’re trying to think of a fun Valentine’s activity, look no further than paint night! Normally associated with a ladies night out (and heavy on the wine), a recent study found that painting releases high levels of the “love hormone”, a.k.a. oxytocin, in men.
Researchers compared the levels of oxytocin with partners painting and partners playing board games, and were surprised by the results: While all the couples released oxytocin during these activities, men in paint class had the highest levels – twice as much as any other group.
Feel free to cite this study next time your man complains about being dragged to a paint-and-sip. Painting partners also experienced more touching than the gaming group (unless you count throwing Monopoly pieces at your significant other as touching).
You won’t get me sick, I’ll get me sick!
There are certain items that, after being used once, you really wouldn’t want to reuse. A snotty, mucus-filled tissue is pretty high up on that list ... or so you would hope. But that’s not thinking with real American entrepreneurial spirit! Welcome to Vaev Tissue, a startup based in Los Angeles that sells used tissues containing germs from a sick person for the bargain price of $79.99.
Yes, you read that correctly. They sell an $80 used tissue. The purpose, according to Vaev’s mission statement, is “to get sick on your own terms,” as “using a tissue that carries a human sneeze is safer than needles or pills.”
As you might expect, the tissues are popular with young parents and adults who are “critical” of vaccines. Who else could hear advice from actual doctors who told Time magazine that “there is nothing positive that can come from this, only things that are adverse,” or that the tissues are an “incredible liability,” and continue on, regardless?
And if you’re thinking, “If these people want to get sick, why not just have someone sneeze on them?” Don’t be ridiculous. Focus testers responded highly negatively to simply being handed a dirty tissue. The premium packaging and high price tag are a necessity.
Our advice? Well, as tempting as all this sounds, we think we’ll stick with washing our hands and not sticking used tissues in our faces. You know, like reasonable people.
Why Bullwinkle thinks pink
Flying squirrels are secretly doing their best flamingo impression – who knew? A forestry professor discovered, by happy accident, that flying squirrels are fluorescent – they glow hot pink under ultraviolet light.
Turns out, almost all species of gliders – even blue-helmeted Rocket “Rocky” J. Squirrel – are members of the Pink Ladies. They are one of the very few glowing mammals; the only other known mammalian species to have fluorescent fur are certain opossums.
But why do these airborne rodents glow pink? Is it because of an overintake of bubblegum? Are flying squirrels just really flamboyant but also shy? Are they huge fans of the singer Pink?
A biologist involved in studying these colorful critters hypothesized that the reason is slightly more related to environment than musical preference. Flying squirrels are nocturnal, making them most active when UV light is most prominent. The garish glow might have something to do with nighttime perception.
However, we don’t know the answer for sure. And in the meantime, we can choose to believe flying squirrels eat way too much cotton candy.
Buzz, feed, diet. Repeat
Guns don’t hurt this mass murderer. Police can’t arrest it. Background checks are pointless. A border wall won’t keep it out. So, how do you stop a mosquito?
Diet drugs.
Because female mosquitoes transmit malaria, Zika, and other diseases when they move from person to person feeding on human blood, investigators sought to curb that appetite by chemically re-creating the feeling of fullness they get after a big meal.
The lady killers in their study – Aedes aegypti, to be exact – when given an antiobesity drug that suppresses human appetite by activating neuropeptide receptors that regulate food intake, turned away from a tempting piece of nylon stocking that had been worn by one of the researchers. Further work showed that treated mosquitoes were as disinterested in feeding on a live mouse as mosquitoes that had already enjoyed a full blood meal.
The LOTME research staff (What? Of course, we have a research staff. You don’t?) is working on the mosquito problem too, although we’ve taken a somewhat different approach: The “volunteers” who walk into the mosquito-filled room wear a sign that says, “My blood will make your butt look bigger.”
Paint me like one of your French girls
If you’re trying to think of a fun Valentine’s activity, look no further than paint night! Normally associated with a ladies night out (and heavy on the wine), a recent study found that painting releases high levels of the “love hormone”, a.k.a. oxytocin, in men.
Researchers compared the levels of oxytocin with partners painting and partners playing board games, and were surprised by the results: While all the couples released oxytocin during these activities, men in paint class had the highest levels – twice as much as any other group.
Feel free to cite this study next time your man complains about being dragged to a paint-and-sip. Painting partners also experienced more touching than the gaming group (unless you count throwing Monopoly pieces at your significant other as touching).
You won’t get me sick, I’ll get me sick!
There are certain items that, after being used once, you really wouldn’t want to reuse. A snotty, mucus-filled tissue is pretty high up on that list ... or so you would hope. But that’s not thinking with real American entrepreneurial spirit! Welcome to Vaev Tissue, a startup based in Los Angeles that sells used tissues containing germs from a sick person for the bargain price of $79.99.
Yes, you read that correctly. They sell an $80 used tissue. The purpose, according to Vaev’s mission statement, is “to get sick on your own terms,” as “using a tissue that carries a human sneeze is safer than needles or pills.”
As you might expect, the tissues are popular with young parents and adults who are “critical” of vaccines. Who else could hear advice from actual doctors who told Time magazine that “there is nothing positive that can come from this, only things that are adverse,” or that the tissues are an “incredible liability,” and continue on, regardless?
And if you’re thinking, “If these people want to get sick, why not just have someone sneeze on them?” Don’t be ridiculous. Focus testers responded highly negatively to simply being handed a dirty tissue. The premium packaging and high price tag are a necessity.
Our advice? Well, as tempting as all this sounds, we think we’ll stick with washing our hands and not sticking used tissues in our faces. You know, like reasonable people.
Why Bullwinkle thinks pink
Flying squirrels are secretly doing their best flamingo impression – who knew? A forestry professor discovered, by happy accident, that flying squirrels are fluorescent – they glow hot pink under ultraviolet light.
Turns out, almost all species of gliders – even blue-helmeted Rocket “Rocky” J. Squirrel – are members of the Pink Ladies. They are one of the very few glowing mammals; the only other known mammalian species to have fluorescent fur are certain opossums.
But why do these airborne rodents glow pink? Is it because of an overintake of bubblegum? Are flying squirrels just really flamboyant but also shy? Are they huge fans of the singer Pink?
A biologist involved in studying these colorful critters hypothesized that the reason is slightly more related to environment than musical preference. Flying squirrels are nocturnal, making them most active when UV light is most prominent. The garish glow might have something to do with nighttime perception.
However, we don’t know the answer for sure. And in the meantime, we can choose to believe flying squirrels eat way too much cotton candy.
Buzz, feed, diet. Repeat
Guns don’t hurt this mass murderer. Police can’t arrest it. Background checks are pointless. A border wall won’t keep it out. So, how do you stop a mosquito?
Diet drugs.
Because female mosquitoes transmit malaria, Zika, and other diseases when they move from person to person feeding on human blood, investigators sought to curb that appetite by chemically re-creating the feeling of fullness they get after a big meal.
The lady killers in their study – Aedes aegypti, to be exact – when given an antiobesity drug that suppresses human appetite by activating neuropeptide receptors that regulate food intake, turned away from a tempting piece of nylon stocking that had been worn by one of the researchers. Further work showed that treated mosquitoes were as disinterested in feeding on a live mouse as mosquitoes that had already enjoyed a full blood meal.
The LOTME research staff (What? Of course, we have a research staff. You don’t?) is working on the mosquito problem too, although we’ve taken a somewhat different approach: The “volunteers” who walk into the mosquito-filled room wear a sign that says, “My blood will make your butt look bigger.”
E-cigarettes beat nicotine patch for smoking cessation
E-cigarettes might be more effective for smoking cessation than nicotine replacement therapy, results of a randomized study of almost 900 adults suggest.
Rates of abstinence at 1 year were 18% for adults who used refillable e-cigarettes to wean themselves off smoking, according to the reported results, compared with about 10% for those who tried nicotine replacement therapies.
“This is particularly noteworthy given that nicotine replacement was used under expert guidance, with access to the full range of nicotine replacement products, and with 88.1% of participants using combination treatments,” said investigator Peter Hajek, PhD, of Queen Mary University of London, and his coauthors in the New England Journal of Medicine.
The findings contrast with those of earlier studies, which showed a lesser effect of e-cigarettes as a stop-smoking strategy, Dr. Hajek and coauthors wrote.
In previous studies, participants used first-generation cartridge-based e-cigarettes, while in the present study, they were given second-generation refillable e-cigarettes and free choice of e-liquids, the authors noted. Moreover, those previous studies provided limited face-to-face support, they said, but
The randomized study by Dr. Hajek and his colleagues included 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service. They were randomized to receive either an e-cigarette starter pack and one bottle of nicotine-containing e-liquid, or 3 months’ worth of nicotine replacement products of their own choosing. At the 52-week validation visits, the study participants received about the equivalence of about $26 U.S. dollars for their travel and time.
Abstinence from smoking at 52 weeks, which was verified by measuring expired carbon monoxide levels, was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001), according to the report.
However, the rate of continued e-cigarette use was “fairly high,” investigators wrote. Eighty percent of the e-cigarette group was still using their assigned product at 52 weeks, compared with just 9% in the nicotine replacement group.
“This can be seen as problematic if e-cigarette use for a year signals long-term use, which may pose as-yet-unknown health risks,” they said.
Tobacco withdrawal symptoms were less severe and satisfaction ratings were higher with e-cigarettes versus nicotine replacement therapy, similar to what had been observed in previous studies, investigators said.
They cited several limitations. For example, product assignments were not blinded. However, the investigators said they tried to “limit expectation effects by recruiting only participants with no strong product preference.”
Dr. Hajek reported grants and fees from Pfizer unrelated to the present study. Coauthors reported disclosures related to Pfizer and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
SOURCE: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.
Any smoking cessation benefit of e-cigarettes needs to be balanced against short- and long-term safety risks of using these products, according to authors of an editorial.
In the study by Hajek et al., the 1-year abstinence rate of 18% in the e-cigarette group compares favorably to what has been reported for Food and Drug Administration–approved smoking cessation treatments, according to Belinda Borelli, PhD, and George T. O’Connor, MD.
The short-term safety data in the trial are “reassuring,” with a low incidence of oropharyngeal irritation, no excess wheezing or dyspnea, and greater declines in cough and phlegm production versus the nicotine replacement group, Dr. Borelli and Dr. O’Connor said.
However, a notable finding was that 80% of participants in the e-cigarette group were still using the product at 1 year, versus just 9% in the nicotine replacement group. “This differential pattern of long-term use raises concerns about the health consequences of long-term e-cigarette use,” they said.
E-cigarette vapor generally has lower levels of toxins and fewer biologic effects than does tobacco smoke, but it has produced adverse biologic effects in animal models and human cells in vitro, according to the authors.
“These findings argue against complacency in accepting the transition from tobacco smoking to indefinite e-cigarette use as a completely successful smoking cessation outcome,” they wrote. Policy analysts need to be careful and do their due diligence to ensure all consequences of the policy options are fully understood, especially as pharmaceuticals account for greater costs in the Medicare program. Future policy analyses must account for changes to Medicare costs as well as beneficiary costs to understand the overall effects of policy changes.
Dr. Borelli is with the Center for Behavioral Science Research, department of health policy and health services research at the Henry M. Goldman School of Dental Medicine, Boston University. Dr. O’Connor is with the Pulmonary Center at Boston University and with the division of pulmonary, allergy, sleep, and critical care medicine at Boston Medical Center. Dr. Borelli had no disclosures; Dr. O’Connor reported disclosures with AstraZeneca and Janssen Pharmaceuticals. They made these comments in an accompanying editorial (N Eng J Med. 2019. doi: 10.1056/NEJMe1816406).
Any smoking cessation benefit of e-cigarettes needs to be balanced against short- and long-term safety risks of using these products, according to authors of an editorial.
In the study by Hajek et al., the 1-year abstinence rate of 18% in the e-cigarette group compares favorably to what has been reported for Food and Drug Administration–approved smoking cessation treatments, according to Belinda Borelli, PhD, and George T. O’Connor, MD.
The short-term safety data in the trial are “reassuring,” with a low incidence of oropharyngeal irritation, no excess wheezing or dyspnea, and greater declines in cough and phlegm production versus the nicotine replacement group, Dr. Borelli and Dr. O’Connor said.
However, a notable finding was that 80% of participants in the e-cigarette group were still using the product at 1 year, versus just 9% in the nicotine replacement group. “This differential pattern of long-term use raises concerns about the health consequences of long-term e-cigarette use,” they said.
E-cigarette vapor generally has lower levels of toxins and fewer biologic effects than does tobacco smoke, but it has produced adverse biologic effects in animal models and human cells in vitro, according to the authors.
“These findings argue against complacency in accepting the transition from tobacco smoking to indefinite e-cigarette use as a completely successful smoking cessation outcome,” they wrote. Policy analysts need to be careful and do their due diligence to ensure all consequences of the policy options are fully understood, especially as pharmaceuticals account for greater costs in the Medicare program. Future policy analyses must account for changes to Medicare costs as well as beneficiary costs to understand the overall effects of policy changes.
Dr. Borelli is with the Center for Behavioral Science Research, department of health policy and health services research at the Henry M. Goldman School of Dental Medicine, Boston University. Dr. O’Connor is with the Pulmonary Center at Boston University and with the division of pulmonary, allergy, sleep, and critical care medicine at Boston Medical Center. Dr. Borelli had no disclosures; Dr. O’Connor reported disclosures with AstraZeneca and Janssen Pharmaceuticals. They made these comments in an accompanying editorial (N Eng J Med. 2019. doi: 10.1056/NEJMe1816406).
Any smoking cessation benefit of e-cigarettes needs to be balanced against short- and long-term safety risks of using these products, according to authors of an editorial.
In the study by Hajek et al., the 1-year abstinence rate of 18% in the e-cigarette group compares favorably to what has been reported for Food and Drug Administration–approved smoking cessation treatments, according to Belinda Borelli, PhD, and George T. O’Connor, MD.
The short-term safety data in the trial are “reassuring,” with a low incidence of oropharyngeal irritation, no excess wheezing or dyspnea, and greater declines in cough and phlegm production versus the nicotine replacement group, Dr. Borelli and Dr. O’Connor said.
However, a notable finding was that 80% of participants in the e-cigarette group were still using the product at 1 year, versus just 9% in the nicotine replacement group. “This differential pattern of long-term use raises concerns about the health consequences of long-term e-cigarette use,” they said.
E-cigarette vapor generally has lower levels of toxins and fewer biologic effects than does tobacco smoke, but it has produced adverse biologic effects in animal models and human cells in vitro, according to the authors.
“These findings argue against complacency in accepting the transition from tobacco smoking to indefinite e-cigarette use as a completely successful smoking cessation outcome,” they wrote. Policy analysts need to be careful and do their due diligence to ensure all consequences of the policy options are fully understood, especially as pharmaceuticals account for greater costs in the Medicare program. Future policy analyses must account for changes to Medicare costs as well as beneficiary costs to understand the overall effects of policy changes.
Dr. Borelli is with the Center for Behavioral Science Research, department of health policy and health services research at the Henry M. Goldman School of Dental Medicine, Boston University. Dr. O’Connor is with the Pulmonary Center at Boston University and with the division of pulmonary, allergy, sleep, and critical care medicine at Boston Medical Center. Dr. Borelli had no disclosures; Dr. O’Connor reported disclosures with AstraZeneca and Janssen Pharmaceuticals. They made these comments in an accompanying editorial (N Eng J Med. 2019. doi: 10.1056/NEJMe1816406).
E-cigarettes might be more effective for smoking cessation than nicotine replacement therapy, results of a randomized study of almost 900 adults suggest.
Rates of abstinence at 1 year were 18% for adults who used refillable e-cigarettes to wean themselves off smoking, according to the reported results, compared with about 10% for those who tried nicotine replacement therapies.
“This is particularly noteworthy given that nicotine replacement was used under expert guidance, with access to the full range of nicotine replacement products, and with 88.1% of participants using combination treatments,” said investigator Peter Hajek, PhD, of Queen Mary University of London, and his coauthors in the New England Journal of Medicine.
The findings contrast with those of earlier studies, which showed a lesser effect of e-cigarettes as a stop-smoking strategy, Dr. Hajek and coauthors wrote.
In previous studies, participants used first-generation cartridge-based e-cigarettes, while in the present study, they were given second-generation refillable e-cigarettes and free choice of e-liquids, the authors noted. Moreover, those previous studies provided limited face-to-face support, they said, but
The randomized study by Dr. Hajek and his colleagues included 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service. They were randomized to receive either an e-cigarette starter pack and one bottle of nicotine-containing e-liquid, or 3 months’ worth of nicotine replacement products of their own choosing. At the 52-week validation visits, the study participants received about the equivalence of about $26 U.S. dollars for their travel and time.
Abstinence from smoking at 52 weeks, which was verified by measuring expired carbon monoxide levels, was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001), according to the report.
However, the rate of continued e-cigarette use was “fairly high,” investigators wrote. Eighty percent of the e-cigarette group was still using their assigned product at 52 weeks, compared with just 9% in the nicotine replacement group.
“This can be seen as problematic if e-cigarette use for a year signals long-term use, which may pose as-yet-unknown health risks,” they said.
Tobacco withdrawal symptoms were less severe and satisfaction ratings were higher with e-cigarettes versus nicotine replacement therapy, similar to what had been observed in previous studies, investigators said.
They cited several limitations. For example, product assignments were not blinded. However, the investigators said they tried to “limit expectation effects by recruiting only participants with no strong product preference.”
Dr. Hajek reported grants and fees from Pfizer unrelated to the present study. Coauthors reported disclosures related to Pfizer and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
SOURCE: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.
E-cigarettes might be more effective for smoking cessation than nicotine replacement therapy, results of a randomized study of almost 900 adults suggest.
Rates of abstinence at 1 year were 18% for adults who used refillable e-cigarettes to wean themselves off smoking, according to the reported results, compared with about 10% for those who tried nicotine replacement therapies.
“This is particularly noteworthy given that nicotine replacement was used under expert guidance, with access to the full range of nicotine replacement products, and with 88.1% of participants using combination treatments,” said investigator Peter Hajek, PhD, of Queen Mary University of London, and his coauthors in the New England Journal of Medicine.
The findings contrast with those of earlier studies, which showed a lesser effect of e-cigarettes as a stop-smoking strategy, Dr. Hajek and coauthors wrote.
In previous studies, participants used first-generation cartridge-based e-cigarettes, while in the present study, they were given second-generation refillable e-cigarettes and free choice of e-liquids, the authors noted. Moreover, those previous studies provided limited face-to-face support, they said, but
The randomized study by Dr. Hajek and his colleagues included 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service. They were randomized to receive either an e-cigarette starter pack and one bottle of nicotine-containing e-liquid, or 3 months’ worth of nicotine replacement products of their own choosing. At the 52-week validation visits, the study participants received about the equivalence of about $26 U.S. dollars for their travel and time.
Abstinence from smoking at 52 weeks, which was verified by measuring expired carbon monoxide levels, was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001), according to the report.
However, the rate of continued e-cigarette use was “fairly high,” investigators wrote. Eighty percent of the e-cigarette group was still using their assigned product at 52 weeks, compared with just 9% in the nicotine replacement group.
“This can be seen as problematic if e-cigarette use for a year signals long-term use, which may pose as-yet-unknown health risks,” they said.
Tobacco withdrawal symptoms were less severe and satisfaction ratings were higher with e-cigarettes versus nicotine replacement therapy, similar to what had been observed in previous studies, investigators said.
They cited several limitations. For example, product assignments were not blinded. However, the investigators said they tried to “limit expectation effects by recruiting only participants with no strong product preference.”
Dr. Hajek reported grants and fees from Pfizer unrelated to the present study. Coauthors reported disclosures related to Pfizer and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
SOURCE: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: The rate of smokers who continued to use e-cigarettes after 1 year was “fairly high,” which might be problematic.
Major finding: Abstinence from smoking at 52 weeks was achieved in 18.0% of the e-cigarette group and 9.9% of the nicotine replacement group (relative risk, 1.83; 95% confidence interval, 1.30-2.58; P less than .001).
Study details: Randomized study of 886 adults in the United Kingdom attending stop-smoking services provided by the U.K. National Health Service.
Disclosures: Dr. Hajek reported grants and fees from Pfizer unrelated to the present study.The coauthors reported disclosures related to Pfizer, and Johnson and Johnson, along with grants from the U.K. National Institute for Health Research.
Source: Hajek P et al. N Engl J Med. 2019;380:629-37. doi: 10.1056/NEJMoa1808779.
What makes women leave surgical training?
LONDON – Being unable to take leave and experiencing poor mental health are just two of the reasons uncovered that may help explain why despite having wanted to be a surgeon for many years, a study of women in surgical training has found. The results were presented at a press briefing and published in a special edition of the Lancet.
These factors are in addition to some previously identified, such as the long working hours, fatigue and sleep deprivation, unpredictable lifestyle and its effects on maintaining personal relationships, and the ability to both start and maintain a family life. Then there are the more serious issues of sexism and discrimination, bullying, and sexual harassment and assault that women face in a still male-dominated field that have been noted in prior studies.
“Women are underrepresented in surgery and leave training in higher proportions than men,” study lead Rhea Liang, MBChB, and coauthors wrote (Lancet. 2019;393:541-9). Previous attempts to understand why this is the case “have been confounded by not fully understanding the problem,” they suggested in the briefing. Their research took a more qualitative and feminist approach than other studies, consulting women who had chosen to leave rather than those who continued their surgical training.
Dr. Liang is a consultant general and breast surgeon based at the Gold Coast Hospital and Health Service in Robina, Australia, who personally interviewed women who had decided to leave their surgical training, some as early as 6 months and others up to 4 years after initiation, for reasons other than underperformance.
A “snowball approach” was used to recruit women whereby women who had agreed to participate were asked to refer others. Although only 12 women were interviewed, it’s quality over quantity, Dr. Liang said in a response to a Twitter comment on the study size. “The study is carried out in Australia where about 300 training places are offered across all the specialties annually. About 30% are women; 20% of those women choose to leave. So, if you do the maths, you’ll see that we actually recruited quite well,” she said at the briefing.
According to The Royal College of Practitioners, women made up a very small percentage of consultant surgeons in England in 2016 (11.1%), which didn’t change much by 2018 (12.2%). This is despite a high percentage (58%) of women being accepted onto university courses in medicine and dentistry (58% in 2016). So why so do so few women end up as surgeons?
“Training is a ‘pinch point’ at which women leave surgery,” Tim Dornan, PhD, noted at the launch of the special edition of the Lancet in which the findings appear. Dr. Dornan is professor of medical and interprofessional education at Queen’s University Belfast (Ireland) and one of the coauthors of the research.
This choice to leave surgery deprives society of able surgeons-to-be,” Dr. Dornan said, noting that there was evidence to suggest that women make as good, if not better, surgeons than men. The decision to leave also deprives women of career opportunities and potentially deprives patients of receiving the best surgical care.
“Something very striking about this research is that women who left within an average of 6-18 months after starting surgical training might have wanted to be surgeons from their teenage years, so it seems something happens at that pinch point which makes women to choose to leave.”
Qualitative research is a good way to understand causality in complex social systems, Dr. Dornan explained. Furthermore, “it’s equitable. If you use an open exploratory method, it’s entirely up to the participants to frame the research, it’s not done a priori, and it has the potential for great policy impact.”
Dr. Liang and team found that multiple factors played a role in the decision to leave surgical training, which on their own might be seemingly small, but when stacked on top of each other formed a tower, which was in danger of toppling after a threshold of three or four factors was reached. To exhaustion and lack of opportunity to learn, for example, could be added bullying, and then being denied leave while it is granted for a male colleague for a similar requested reason. The cumulative impact of these factors may all add up to create the impetus to leave.
“Just as a tower of blocks can rebalanced with small adjustments, out study indicates that relatively small interventions (e.g., a cup of tea or a supportive chat) could have been effective in preventing them choosing to leave,” she said.
However, they advocate targeting interventions at all trainees and not just women, to reduce gender differences as focusing on women would be more likely to exaggerate the “otherness” of women further and alienate male trainees. They suggest: “Women might be best helped by interventions that are alert to the possibility of unplanned negative effects, do not unduly focus on gender, and address multiple factors.”
“If you really want to benefit women you should benefit everybody and address the root problem, which is the harsh conditions of training,” Dr. Dornan said. “The prediction would be that, if you do that, then you will actually retain men as well as women.”
The research appears in a special edition of the Lancet that promotes advancing women in science, medicine, and global health.
SOURCE: Liang R et al. Lancet. 2019;393:541-9.
LONDON – Being unable to take leave and experiencing poor mental health are just two of the reasons uncovered that may help explain why despite having wanted to be a surgeon for many years, a study of women in surgical training has found. The results were presented at a press briefing and published in a special edition of the Lancet.
These factors are in addition to some previously identified, such as the long working hours, fatigue and sleep deprivation, unpredictable lifestyle and its effects on maintaining personal relationships, and the ability to both start and maintain a family life. Then there are the more serious issues of sexism and discrimination, bullying, and sexual harassment and assault that women face in a still male-dominated field that have been noted in prior studies.
“Women are underrepresented in surgery and leave training in higher proportions than men,” study lead Rhea Liang, MBChB, and coauthors wrote (Lancet. 2019;393:541-9). Previous attempts to understand why this is the case “have been confounded by not fully understanding the problem,” they suggested in the briefing. Their research took a more qualitative and feminist approach than other studies, consulting women who had chosen to leave rather than those who continued their surgical training.
Dr. Liang is a consultant general and breast surgeon based at the Gold Coast Hospital and Health Service in Robina, Australia, who personally interviewed women who had decided to leave their surgical training, some as early as 6 months and others up to 4 years after initiation, for reasons other than underperformance.
A “snowball approach” was used to recruit women whereby women who had agreed to participate were asked to refer others. Although only 12 women were interviewed, it’s quality over quantity, Dr. Liang said in a response to a Twitter comment on the study size. “The study is carried out in Australia where about 300 training places are offered across all the specialties annually. About 30% are women; 20% of those women choose to leave. So, if you do the maths, you’ll see that we actually recruited quite well,” she said at the briefing.
According to The Royal College of Practitioners, women made up a very small percentage of consultant surgeons in England in 2016 (11.1%), which didn’t change much by 2018 (12.2%). This is despite a high percentage (58%) of women being accepted onto university courses in medicine and dentistry (58% in 2016). So why so do so few women end up as surgeons?
“Training is a ‘pinch point’ at which women leave surgery,” Tim Dornan, PhD, noted at the launch of the special edition of the Lancet in which the findings appear. Dr. Dornan is professor of medical and interprofessional education at Queen’s University Belfast (Ireland) and one of the coauthors of the research.
This choice to leave surgery deprives society of able surgeons-to-be,” Dr. Dornan said, noting that there was evidence to suggest that women make as good, if not better, surgeons than men. The decision to leave also deprives women of career opportunities and potentially deprives patients of receiving the best surgical care.
“Something very striking about this research is that women who left within an average of 6-18 months after starting surgical training might have wanted to be surgeons from their teenage years, so it seems something happens at that pinch point which makes women to choose to leave.”
Qualitative research is a good way to understand causality in complex social systems, Dr. Dornan explained. Furthermore, “it’s equitable. If you use an open exploratory method, it’s entirely up to the participants to frame the research, it’s not done a priori, and it has the potential for great policy impact.”
Dr. Liang and team found that multiple factors played a role in the decision to leave surgical training, which on their own might be seemingly small, but when stacked on top of each other formed a tower, which was in danger of toppling after a threshold of three or four factors was reached. To exhaustion and lack of opportunity to learn, for example, could be added bullying, and then being denied leave while it is granted for a male colleague for a similar requested reason. The cumulative impact of these factors may all add up to create the impetus to leave.
“Just as a tower of blocks can rebalanced with small adjustments, out study indicates that relatively small interventions (e.g., a cup of tea or a supportive chat) could have been effective in preventing them choosing to leave,” she said.
However, they advocate targeting interventions at all trainees and not just women, to reduce gender differences as focusing on women would be more likely to exaggerate the “otherness” of women further and alienate male trainees. They suggest: “Women might be best helped by interventions that are alert to the possibility of unplanned negative effects, do not unduly focus on gender, and address multiple factors.”
“If you really want to benefit women you should benefit everybody and address the root problem, which is the harsh conditions of training,” Dr. Dornan said. “The prediction would be that, if you do that, then you will actually retain men as well as women.”
The research appears in a special edition of the Lancet that promotes advancing women in science, medicine, and global health.
SOURCE: Liang R et al. Lancet. 2019;393:541-9.
LONDON – Being unable to take leave and experiencing poor mental health are just two of the reasons uncovered that may help explain why despite having wanted to be a surgeon for many years, a study of women in surgical training has found. The results were presented at a press briefing and published in a special edition of the Lancet.
These factors are in addition to some previously identified, such as the long working hours, fatigue and sleep deprivation, unpredictable lifestyle and its effects on maintaining personal relationships, and the ability to both start and maintain a family life. Then there are the more serious issues of sexism and discrimination, bullying, and sexual harassment and assault that women face in a still male-dominated field that have been noted in prior studies.
“Women are underrepresented in surgery and leave training in higher proportions than men,” study lead Rhea Liang, MBChB, and coauthors wrote (Lancet. 2019;393:541-9). Previous attempts to understand why this is the case “have been confounded by not fully understanding the problem,” they suggested in the briefing. Their research took a more qualitative and feminist approach than other studies, consulting women who had chosen to leave rather than those who continued their surgical training.
Dr. Liang is a consultant general and breast surgeon based at the Gold Coast Hospital and Health Service in Robina, Australia, who personally interviewed women who had decided to leave their surgical training, some as early as 6 months and others up to 4 years after initiation, for reasons other than underperformance.
A “snowball approach” was used to recruit women whereby women who had agreed to participate were asked to refer others. Although only 12 women were interviewed, it’s quality over quantity, Dr. Liang said in a response to a Twitter comment on the study size. “The study is carried out in Australia where about 300 training places are offered across all the specialties annually. About 30% are women; 20% of those women choose to leave. So, if you do the maths, you’ll see that we actually recruited quite well,” she said at the briefing.
According to The Royal College of Practitioners, women made up a very small percentage of consultant surgeons in England in 2016 (11.1%), which didn’t change much by 2018 (12.2%). This is despite a high percentage (58%) of women being accepted onto university courses in medicine and dentistry (58% in 2016). So why so do so few women end up as surgeons?
“Training is a ‘pinch point’ at which women leave surgery,” Tim Dornan, PhD, noted at the launch of the special edition of the Lancet in which the findings appear. Dr. Dornan is professor of medical and interprofessional education at Queen’s University Belfast (Ireland) and one of the coauthors of the research.
This choice to leave surgery deprives society of able surgeons-to-be,” Dr. Dornan said, noting that there was evidence to suggest that women make as good, if not better, surgeons than men. The decision to leave also deprives women of career opportunities and potentially deprives patients of receiving the best surgical care.
“Something very striking about this research is that women who left within an average of 6-18 months after starting surgical training might have wanted to be surgeons from their teenage years, so it seems something happens at that pinch point which makes women to choose to leave.”
Qualitative research is a good way to understand causality in complex social systems, Dr. Dornan explained. Furthermore, “it’s equitable. If you use an open exploratory method, it’s entirely up to the participants to frame the research, it’s not done a priori, and it has the potential for great policy impact.”
Dr. Liang and team found that multiple factors played a role in the decision to leave surgical training, which on their own might be seemingly small, but when stacked on top of each other formed a tower, which was in danger of toppling after a threshold of three or four factors was reached. To exhaustion and lack of opportunity to learn, for example, could be added bullying, and then being denied leave while it is granted for a male colleague for a similar requested reason. The cumulative impact of these factors may all add up to create the impetus to leave.
“Just as a tower of blocks can rebalanced with small adjustments, out study indicates that relatively small interventions (e.g., a cup of tea or a supportive chat) could have been effective in preventing them choosing to leave,” she said.
However, they advocate targeting interventions at all trainees and not just women, to reduce gender differences as focusing on women would be more likely to exaggerate the “otherness” of women further and alienate male trainees. They suggest: “Women might be best helped by interventions that are alert to the possibility of unplanned negative effects, do not unduly focus on gender, and address multiple factors.”
“If you really want to benefit women you should benefit everybody and address the root problem, which is the harsh conditions of training,” Dr. Dornan said. “The prediction would be that, if you do that, then you will actually retain men as well as women.”
The research appears in a special edition of the Lancet that promotes advancing women in science, medicine, and global health.
SOURCE: Liang R et al. Lancet. 2019;393:541-9.
FROM A LAUNCH EVENT HELD BY THE LANCET
Key clinical point: Women leave surgical training for multiple reasons; interventions should focus on surgical training conditions not gender.
Major finding: Six new reasons identified: unavailability of leave; a distinction between valid and invalid reasons for leave; poor mental health; absence of interactions with women in surgery section and other supports; fear of repercussion; lack of pathways for independent and specific support.
Study details: Qualitative study of 12 women who chose to leave their surgical training after 6 months to 4 years.
Disclosures: No financial conflicts of interest were reported.
Source: Liang R et al. Lancet. 2019;393:541-9.
Irregularly Hyperpigmented Plaque on the Right Heel
The Diagnosis: Pigmented Bowen Disease
A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).
Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.3 Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.5 In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.
Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.7 Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.8
The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.6 Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).
In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.
- Cameron A, Rosendahl C, Tschandl P, et al. Dermatoscopy of pigmented Bowen’s disease [published online January 15, 2010]. J Am Acad Dermatol. 2010;62:597-604.
- Ragi G, Turner MS, Klein LE, et al. Pigmented Bowen’s disease and review of 420 Bowen’s disease lesions. J Dermatol Surg Oncol. 1988;14:765-769.
- Hernandez C, Ivkovic A, Fowler A. Growing plaque on foot. J Fam Pract. 2008;57:603-605.
- Hwang SW, Kim JW, Park SW, et al. Two cases of pigmented Bowen’s disease. Ann Dermatol 2002;14:127-129.
- Wilmer EM, Lee KC, Higgins W 2nd, et al. Hyperpigmented palmar plaque: an unexpected diagnosis of Bowen disease. Dermatol Online J. 2013;19:18573.
- Brinca A, Teixeira V, Gonçalo M, et al. A large pigmented lesion mimicking malignant melanoma. Clin Exp Dermatol. 2012;37:817-884.
- Hilliard NJ, Huang C, Andea A. Pigmented extramammary Paget’s disease of the axilla mimicking melanoma: case report and review of the literature. J Cutan Pathol. 2009;36:995-1000.
- Öztürk Durmaz E, Dog˘ an Ekici I, Ozian F, et al. Pigmented Bowen’s disease of the genitalia masquerading as malignant melanoma. Acta Dermatovenerol Croat. 2015;23:130-133.
The Diagnosis: Pigmented Bowen Disease
A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).
Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.3 Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.5 In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.
Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.7 Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.8
The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.6 Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).
In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.
The Diagnosis: Pigmented Bowen Disease
A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).
Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.3 Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.5 In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.
Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.7 Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.8
The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.6 Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).
In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.
- Cameron A, Rosendahl C, Tschandl P, et al. Dermatoscopy of pigmented Bowen’s disease [published online January 15, 2010]. J Am Acad Dermatol. 2010;62:597-604.
- Ragi G, Turner MS, Klein LE, et al. Pigmented Bowen’s disease and review of 420 Bowen’s disease lesions. J Dermatol Surg Oncol. 1988;14:765-769.
- Hernandez C, Ivkovic A, Fowler A. Growing plaque on foot. J Fam Pract. 2008;57:603-605.
- Hwang SW, Kim JW, Park SW, et al. Two cases of pigmented Bowen’s disease. Ann Dermatol 2002;14:127-129.
- Wilmer EM, Lee KC, Higgins W 2nd, et al. Hyperpigmented palmar plaque: an unexpected diagnosis of Bowen disease. Dermatol Online J. 2013;19:18573.
- Brinca A, Teixeira V, Gonçalo M, et al. A large pigmented lesion mimicking malignant melanoma. Clin Exp Dermatol. 2012;37:817-884.
- Hilliard NJ, Huang C, Andea A. Pigmented extramammary Paget’s disease of the axilla mimicking melanoma: case report and review of the literature. J Cutan Pathol. 2009;36:995-1000.
- Öztürk Durmaz E, Dog˘ an Ekici I, Ozian F, et al. Pigmented Bowen’s disease of the genitalia masquerading as malignant melanoma. Acta Dermatovenerol Croat. 2015;23:130-133.
- Cameron A, Rosendahl C, Tschandl P, et al. Dermatoscopy of pigmented Bowen’s disease [published online January 15, 2010]. J Am Acad Dermatol. 2010;62:597-604.
- Ragi G, Turner MS, Klein LE, et al. Pigmented Bowen’s disease and review of 420 Bowen’s disease lesions. J Dermatol Surg Oncol. 1988;14:765-769.
- Hernandez C, Ivkovic A, Fowler A. Growing plaque on foot. J Fam Pract. 2008;57:603-605.
- Hwang SW, Kim JW, Park SW, et al. Two cases of pigmented Bowen’s disease. Ann Dermatol 2002;14:127-129.
- Wilmer EM, Lee KC, Higgins W 2nd, et al. Hyperpigmented palmar plaque: an unexpected diagnosis of Bowen disease. Dermatol Online J. 2013;19:18573.
- Brinca A, Teixeira V, Gonçalo M, et al. A large pigmented lesion mimicking malignant melanoma. Clin Exp Dermatol. 2012;37:817-884.
- Hilliard NJ, Huang C, Andea A. Pigmented extramammary Paget’s disease of the axilla mimicking melanoma: case report and review of the literature. J Cutan Pathol. 2009;36:995-1000.
- Öztürk Durmaz E, Dog˘ an Ekici I, Ozian F, et al. Pigmented Bowen’s disease of the genitalia masquerading as malignant melanoma. Acta Dermatovenerol Croat. 2015;23:130-133.
A 56-year-old woman presented with an asymptomatic plaque on the right heel that had grown
steadily over the last year. Pigmented lesions were not appreciated on other sites, and lymph nodes were not enlarged. Her medical history was otherwise normal, except for bilateral hearing loss due to encephalitis at the age of 5 years. None of her family members had similar symptoms. Physical examination revealed a well-defined, irregularly hyperpigmented plaque on the right heel.
