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Old theories spark new ideas about cancer cell metabolism
It has long been understood that cancer cells have a different metabolism from that of normal cells, but this was widely thought to be a by-product of the genetic alterations that are the suspected drivers of cancer development.
Though early proponents of tumor metabolism argued that cancer was fundamentally a metabolic disease, this idea was sidetracked as we entered the genome-sequencing era and focused on precision medicine. In the past decade, however, we’ve come full circle as many researchers have again begun to advocate for a revival of the idea that tumor metabolism might represent a root cause of cancer.
“Altered metabolism can be both a cause and an effect that is essential for cancer progression,” Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said in an interview.
Cancer’s sweet tooth
The unique metabolism of cancer cells was first highlighted almost a century ago by the German physiologist Dr. Otto Warburg. He noticed that cancer cells change the way they derive energy from glucose. Typically, cells use glycolysis to convert glucose into pyruvate in the cytoplasm. The pyruvate is then fed into the mitochondria to produce energy through oxidative phosphorylation, which requires oxygen. When oxygen levels are low, cells are able to make energy through glycolysis, but this is much less efficient, yielding far less energy for each glucose molecule consumed.
Cancer cells, however, seem to prefer to use glycolysis, even when oxygen is plentiful, and in order to compensate for the fact that glycolysis produces significantly less energy, the cancer cells take up much more glucose than their normal counterparts.
Dr. Warburg’s rationale was that cancer cells use glycolysis because their mitochondria are damaged, and he even proposed that this defect was “the root cause of cancer,” that the genetic dysregulation of cancer cells could be traced to impaired respiration and energy metabolism. In fact, it turned out that mitochondria, for the most part, are intact in cancer cells, and, because the “Warburg effect,” as it has come to be known, didn’t fully explain how cancer develops, it was written off as an effect of cancer, rather than the cause.
Beyond the Warburg effect
As we have added to our understanding of how cancer develops, it has become increasingly clear that many of the drivers of tumorigenesis are intricately linked to cellular metabolism, which has renewed interest in Warburg’s hypothesis and in tumor metabolism.
Because the Warburg effect didn’t appear to be an adaptation to defective respiration, the question remained as to why cancer cells would use a less efficient method of energy production. The answer, at least in part, is that they aren’t just using it to make energy.
Cancer cells are growing and dividing very rapidly, and they need a quick and efficient means of producing all of the metabolic building blocks they need to do this. Using glycolysis is a trade-off between making less energy and making it more quickly. Furthermore, the conversion of glucose into pyruvate via glycolysis occurs through several intermediates that can be diverted into other biosynthetic pathways that produce some of those much needed building blocks required to produce essential cellular components.
Although the Warburg effect is still the best characterized metabolic distinction in cancer cells, it can now be added to a growing number of dysregulated metabolic processes.
“Cancer’s sweet tooth is not the entire picture,” said Dr. Dang, “because cells are made of more than just carbon, hydrogen, and oxygen.” Research has shown that there is a fundamental change in the metabolism of all four major classes of macromolecules – carbohydrates, proteins, lipids, and nucleic acids. Cancer-associated alterations have been shown to encompass all aspects of cellular metabolism, increasing the ability of tumors to acquire nutrients, but also dictating how those nutrients are used.
As the understanding of tumor metabolism is growing, so too is an appreciation of its heterogeneity. Not all tumor types and, indeed, not all cells within the same tumor, will display the same metabolic profile. The metabolic needs of a tumor can depend upon nutrient availability, the influence of its surrounding environment, and the distance to the nearest blood vessels.
The selfish cell
Many researchers have also begun to reexamine the idea that tumor metabolism is more than just a hallmark of cancer. On the one hand, Dr. Dang explained, “there are mutations in genes that affect mitochondrial function that leads to cancer and in metabolic enzymes that in turn trigger cancer development through altering the epigenome.” On the other hand, “cancer genes – oncogenes and tumor suppressor genes that drive cancer development – can alter cancer cell metabolism to support cancer cell growth.” Hence, one can argue for a role of tumor metabolism as both a cause of tumor growth and one of the many effects of the genetic mutability of cancer.
An example of a widely studied gene that has turned out to be vital to tumor metabolism is the MYC oncogene that encodes a transcription factor with a well-known role in cell cycle progression. It turns out, said Dr. Dang, that “MYC opens up the fuel line to drive cell growth; it drives genes that import nutrients into cells and metabolize nutrients to make the building blocks for the growing cell.”
Many of the growth factor signaling pathways that are commonly dysregulated in cancer don’t just regulate cell growth and proliferation, but are also intimately involved in dictating the response to nutrients. A prominent example is the PI3K/Akt pathway; among the most highly mutated pathways in human cancer, it acts as a master regulator of glucose uptake.
Some researchers propose that alterations in growth factor signaling pathways drive cancer formation because they allow the cell to flaunt the rules of the dinner table. Essentially, instead of acting like a cell that forms part of a multicellular organism, taking cues from the surrounding cells about when and how to respond to nutrients, cancer cells are able to ignore these signals and take up whatever nutrients they can find. This may also explain the observation that cancer development is closely linked to obesity and diabetes.
Targeting metabolism
These discoveries have led researchers to consider the possibility of targeting metabolism to prevent cancer cell growth. Some commonly used chemotherapy drugs have a metabolic mechanism of action; the antifolates methotrexate and pemetrexed, for example, target one-carbon metabolism.
Although no metabolism-based small-molecule drugs are approved yet, many are in preclinical development, and some are beginning to move forward into clinical trials. Dr. Dang highlighted the development of drugs targeting metabolic enzymes: “Drugs being developed against the mutant enzymes IDH1/2 have demonstrated clinical responses in acute myelocytic leukemia, and other drugs, such as CB-839 – an inhibitor of glutaminase – are undergoing clinical studies.”
Several existing drugs have also been repurposed in the fight against cancer, including some not previously thought of in this context, such as the antidiabetic drug metformin, which has shown significant promise. Dr. Dang concluded: “The future outlook is the generation of a new class of drugs that could, in combination with other drugs, result in better clinical treatments for cancers.”
It has long been understood that cancer cells have a different metabolism from that of normal cells, but this was widely thought to be a by-product of the genetic alterations that are the suspected drivers of cancer development.
Though early proponents of tumor metabolism argued that cancer was fundamentally a metabolic disease, this idea was sidetracked as we entered the genome-sequencing era and focused on precision medicine. In the past decade, however, we’ve come full circle as many researchers have again begun to advocate for a revival of the idea that tumor metabolism might represent a root cause of cancer.
“Altered metabolism can be both a cause and an effect that is essential for cancer progression,” Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said in an interview.
Cancer’s sweet tooth
The unique metabolism of cancer cells was first highlighted almost a century ago by the German physiologist Dr. Otto Warburg. He noticed that cancer cells change the way they derive energy from glucose. Typically, cells use glycolysis to convert glucose into pyruvate in the cytoplasm. The pyruvate is then fed into the mitochondria to produce energy through oxidative phosphorylation, which requires oxygen. When oxygen levels are low, cells are able to make energy through glycolysis, but this is much less efficient, yielding far less energy for each glucose molecule consumed.
Cancer cells, however, seem to prefer to use glycolysis, even when oxygen is plentiful, and in order to compensate for the fact that glycolysis produces significantly less energy, the cancer cells take up much more glucose than their normal counterparts.
Dr. Warburg’s rationale was that cancer cells use glycolysis because their mitochondria are damaged, and he even proposed that this defect was “the root cause of cancer,” that the genetic dysregulation of cancer cells could be traced to impaired respiration and energy metabolism. In fact, it turned out that mitochondria, for the most part, are intact in cancer cells, and, because the “Warburg effect,” as it has come to be known, didn’t fully explain how cancer develops, it was written off as an effect of cancer, rather than the cause.
Beyond the Warburg effect
As we have added to our understanding of how cancer develops, it has become increasingly clear that many of the drivers of tumorigenesis are intricately linked to cellular metabolism, which has renewed interest in Warburg’s hypothesis and in tumor metabolism.
Because the Warburg effect didn’t appear to be an adaptation to defective respiration, the question remained as to why cancer cells would use a less efficient method of energy production. The answer, at least in part, is that they aren’t just using it to make energy.
Cancer cells are growing and dividing very rapidly, and they need a quick and efficient means of producing all of the metabolic building blocks they need to do this. Using glycolysis is a trade-off between making less energy and making it more quickly. Furthermore, the conversion of glucose into pyruvate via glycolysis occurs through several intermediates that can be diverted into other biosynthetic pathways that produce some of those much needed building blocks required to produce essential cellular components.
Although the Warburg effect is still the best characterized metabolic distinction in cancer cells, it can now be added to a growing number of dysregulated metabolic processes.
“Cancer’s sweet tooth is not the entire picture,” said Dr. Dang, “because cells are made of more than just carbon, hydrogen, and oxygen.” Research has shown that there is a fundamental change in the metabolism of all four major classes of macromolecules – carbohydrates, proteins, lipids, and nucleic acids. Cancer-associated alterations have been shown to encompass all aspects of cellular metabolism, increasing the ability of tumors to acquire nutrients, but also dictating how those nutrients are used.
As the understanding of tumor metabolism is growing, so too is an appreciation of its heterogeneity. Not all tumor types and, indeed, not all cells within the same tumor, will display the same metabolic profile. The metabolic needs of a tumor can depend upon nutrient availability, the influence of its surrounding environment, and the distance to the nearest blood vessels.
The selfish cell
Many researchers have also begun to reexamine the idea that tumor metabolism is more than just a hallmark of cancer. On the one hand, Dr. Dang explained, “there are mutations in genes that affect mitochondrial function that leads to cancer and in metabolic enzymes that in turn trigger cancer development through altering the epigenome.” On the other hand, “cancer genes – oncogenes and tumor suppressor genes that drive cancer development – can alter cancer cell metabolism to support cancer cell growth.” Hence, one can argue for a role of tumor metabolism as both a cause of tumor growth and one of the many effects of the genetic mutability of cancer.
An example of a widely studied gene that has turned out to be vital to tumor metabolism is the MYC oncogene that encodes a transcription factor with a well-known role in cell cycle progression. It turns out, said Dr. Dang, that “MYC opens up the fuel line to drive cell growth; it drives genes that import nutrients into cells and metabolize nutrients to make the building blocks for the growing cell.”
Many of the growth factor signaling pathways that are commonly dysregulated in cancer don’t just regulate cell growth and proliferation, but are also intimately involved in dictating the response to nutrients. A prominent example is the PI3K/Akt pathway; among the most highly mutated pathways in human cancer, it acts as a master regulator of glucose uptake.
Some researchers propose that alterations in growth factor signaling pathways drive cancer formation because they allow the cell to flaunt the rules of the dinner table. Essentially, instead of acting like a cell that forms part of a multicellular organism, taking cues from the surrounding cells about when and how to respond to nutrients, cancer cells are able to ignore these signals and take up whatever nutrients they can find. This may also explain the observation that cancer development is closely linked to obesity and diabetes.
Targeting metabolism
These discoveries have led researchers to consider the possibility of targeting metabolism to prevent cancer cell growth. Some commonly used chemotherapy drugs have a metabolic mechanism of action; the antifolates methotrexate and pemetrexed, for example, target one-carbon metabolism.
Although no metabolism-based small-molecule drugs are approved yet, many are in preclinical development, and some are beginning to move forward into clinical trials. Dr. Dang highlighted the development of drugs targeting metabolic enzymes: “Drugs being developed against the mutant enzymes IDH1/2 have demonstrated clinical responses in acute myelocytic leukemia, and other drugs, such as CB-839 – an inhibitor of glutaminase – are undergoing clinical studies.”
Several existing drugs have also been repurposed in the fight against cancer, including some not previously thought of in this context, such as the antidiabetic drug metformin, which has shown significant promise. Dr. Dang concluded: “The future outlook is the generation of a new class of drugs that could, in combination with other drugs, result in better clinical treatments for cancers.”
It has long been understood that cancer cells have a different metabolism from that of normal cells, but this was widely thought to be a by-product of the genetic alterations that are the suspected drivers of cancer development.
Though early proponents of tumor metabolism argued that cancer was fundamentally a metabolic disease, this idea was sidetracked as we entered the genome-sequencing era and focused on precision medicine. In the past decade, however, we’ve come full circle as many researchers have again begun to advocate for a revival of the idea that tumor metabolism might represent a root cause of cancer.
“Altered metabolism can be both a cause and an effect that is essential for cancer progression,” Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said in an interview.
Cancer’s sweet tooth
The unique metabolism of cancer cells was first highlighted almost a century ago by the German physiologist Dr. Otto Warburg. He noticed that cancer cells change the way they derive energy from glucose. Typically, cells use glycolysis to convert glucose into pyruvate in the cytoplasm. The pyruvate is then fed into the mitochondria to produce energy through oxidative phosphorylation, which requires oxygen. When oxygen levels are low, cells are able to make energy through glycolysis, but this is much less efficient, yielding far less energy for each glucose molecule consumed.
Cancer cells, however, seem to prefer to use glycolysis, even when oxygen is plentiful, and in order to compensate for the fact that glycolysis produces significantly less energy, the cancer cells take up much more glucose than their normal counterparts.
Dr. Warburg’s rationale was that cancer cells use glycolysis because their mitochondria are damaged, and he even proposed that this defect was “the root cause of cancer,” that the genetic dysregulation of cancer cells could be traced to impaired respiration and energy metabolism. In fact, it turned out that mitochondria, for the most part, are intact in cancer cells, and, because the “Warburg effect,” as it has come to be known, didn’t fully explain how cancer develops, it was written off as an effect of cancer, rather than the cause.
Beyond the Warburg effect
As we have added to our understanding of how cancer develops, it has become increasingly clear that many of the drivers of tumorigenesis are intricately linked to cellular metabolism, which has renewed interest in Warburg’s hypothesis and in tumor metabolism.
Because the Warburg effect didn’t appear to be an adaptation to defective respiration, the question remained as to why cancer cells would use a less efficient method of energy production. The answer, at least in part, is that they aren’t just using it to make energy.
Cancer cells are growing and dividing very rapidly, and they need a quick and efficient means of producing all of the metabolic building blocks they need to do this. Using glycolysis is a trade-off between making less energy and making it more quickly. Furthermore, the conversion of glucose into pyruvate via glycolysis occurs through several intermediates that can be diverted into other biosynthetic pathways that produce some of those much needed building blocks required to produce essential cellular components.
Although the Warburg effect is still the best characterized metabolic distinction in cancer cells, it can now be added to a growing number of dysregulated metabolic processes.
“Cancer’s sweet tooth is not the entire picture,” said Dr. Dang, “because cells are made of more than just carbon, hydrogen, and oxygen.” Research has shown that there is a fundamental change in the metabolism of all four major classes of macromolecules – carbohydrates, proteins, lipids, and nucleic acids. Cancer-associated alterations have been shown to encompass all aspects of cellular metabolism, increasing the ability of tumors to acquire nutrients, but also dictating how those nutrients are used.
As the understanding of tumor metabolism is growing, so too is an appreciation of its heterogeneity. Not all tumor types and, indeed, not all cells within the same tumor, will display the same metabolic profile. The metabolic needs of a tumor can depend upon nutrient availability, the influence of its surrounding environment, and the distance to the nearest blood vessels.
The selfish cell
Many researchers have also begun to reexamine the idea that tumor metabolism is more than just a hallmark of cancer. On the one hand, Dr. Dang explained, “there are mutations in genes that affect mitochondrial function that leads to cancer and in metabolic enzymes that in turn trigger cancer development through altering the epigenome.” On the other hand, “cancer genes – oncogenes and tumor suppressor genes that drive cancer development – can alter cancer cell metabolism to support cancer cell growth.” Hence, one can argue for a role of tumor metabolism as both a cause of tumor growth and one of the many effects of the genetic mutability of cancer.
An example of a widely studied gene that has turned out to be vital to tumor metabolism is the MYC oncogene that encodes a transcription factor with a well-known role in cell cycle progression. It turns out, said Dr. Dang, that “MYC opens up the fuel line to drive cell growth; it drives genes that import nutrients into cells and metabolize nutrients to make the building blocks for the growing cell.”
Many of the growth factor signaling pathways that are commonly dysregulated in cancer don’t just regulate cell growth and proliferation, but are also intimately involved in dictating the response to nutrients. A prominent example is the PI3K/Akt pathway; among the most highly mutated pathways in human cancer, it acts as a master regulator of glucose uptake.
Some researchers propose that alterations in growth factor signaling pathways drive cancer formation because they allow the cell to flaunt the rules of the dinner table. Essentially, instead of acting like a cell that forms part of a multicellular organism, taking cues from the surrounding cells about when and how to respond to nutrients, cancer cells are able to ignore these signals and take up whatever nutrients they can find. This may also explain the observation that cancer development is closely linked to obesity and diabetes.
Targeting metabolism
These discoveries have led researchers to consider the possibility of targeting metabolism to prevent cancer cell growth. Some commonly used chemotherapy drugs have a metabolic mechanism of action; the antifolates methotrexate and pemetrexed, for example, target one-carbon metabolism.
Although no metabolism-based small-molecule drugs are approved yet, many are in preclinical development, and some are beginning to move forward into clinical trials. Dr. Dang highlighted the development of drugs targeting metabolic enzymes: “Drugs being developed against the mutant enzymes IDH1/2 have demonstrated clinical responses in acute myelocytic leukemia, and other drugs, such as CB-839 – an inhibitor of glutaminase – are undergoing clinical studies.”
Several existing drugs have also been repurposed in the fight against cancer, including some not previously thought of in this context, such as the antidiabetic drug metformin, which has shown significant promise. Dr. Dang concluded: “The future outlook is the generation of a new class of drugs that could, in combination with other drugs, result in better clinical treatments for cancers.”
Venetoclax achieves responses in CLL refractory to ibrutinib, idelalisib
Venetoclax monotherapy was active, and even elicited minimal residual disease negativity in a proportion of patients with chronic lymphocytic leukemia (CLL) that was resistant or refractory to ibrutinib or idelalisib, Dr. Jeffrey Alan Jones of the Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in an abstract to be presented at the annual meeting of the American Society of Clinical Oncology.
The findings from their ongoing phase II study are the first prospective results to demonstrate efficacy in this poor-prognosis population, the researchers wrote. Earlier results from the study were reported at the American Society of Hematology meeting.
The 54 patients in the study, 25 of them refractory to ibrutinib and 6 to idelalisib, received venetoclax 20 mg daily followed by a 5-week ramp up in dosage to 400 mg daily. Over half of the patients had received more than five prior therapies; 83% did not have IGHV mutations, 20% had absolute lymphocyte counts exceeding 100 x 109, 35% had 17p deletions, and 24% had at least one node that was 10 cm or larger.
Of the patients who had previously received ibrutinib, four discontinued venetoclax because of progressive disease and four others had respiratory failure, multiorgan failure, death of unknown cause, or consent withdrawal. Of those who previously received idelalisib, four halted therapy because of progressive disease and failure to respond. Of 48 evaluable patients, 38 previously received ibrutinib, and 10 previously received idelalisib.
The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib.
Grade 3/4 adverse events were seen in over 10% of patients and included neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%). Significant adverse events seen in at least two patients included pneumonia (9%), febrile neutropenia (7%), increased potassium, multiorgan failure, and septic shock (4% each).
The study is sponsored by AbbVie.
Venetoclax monotherapy was active, and even elicited minimal residual disease negativity in a proportion of patients with chronic lymphocytic leukemia (CLL) that was resistant or refractory to ibrutinib or idelalisib, Dr. Jeffrey Alan Jones of the Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in an abstract to be presented at the annual meeting of the American Society of Clinical Oncology.
The findings from their ongoing phase II study are the first prospective results to demonstrate efficacy in this poor-prognosis population, the researchers wrote. Earlier results from the study were reported at the American Society of Hematology meeting.
The 54 patients in the study, 25 of them refractory to ibrutinib and 6 to idelalisib, received venetoclax 20 mg daily followed by a 5-week ramp up in dosage to 400 mg daily. Over half of the patients had received more than five prior therapies; 83% did not have IGHV mutations, 20% had absolute lymphocyte counts exceeding 100 x 109, 35% had 17p deletions, and 24% had at least one node that was 10 cm or larger.
Of the patients who had previously received ibrutinib, four discontinued venetoclax because of progressive disease and four others had respiratory failure, multiorgan failure, death of unknown cause, or consent withdrawal. Of those who previously received idelalisib, four halted therapy because of progressive disease and failure to respond. Of 48 evaluable patients, 38 previously received ibrutinib, and 10 previously received idelalisib.
The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib.
Grade 3/4 adverse events were seen in over 10% of patients and included neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%). Significant adverse events seen in at least two patients included pneumonia (9%), febrile neutropenia (7%), increased potassium, multiorgan failure, and septic shock (4% each).
The study is sponsored by AbbVie.
Venetoclax monotherapy was active, and even elicited minimal residual disease negativity in a proportion of patients with chronic lymphocytic leukemia (CLL) that was resistant or refractory to ibrutinib or idelalisib, Dr. Jeffrey Alan Jones of the Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in an abstract to be presented at the annual meeting of the American Society of Clinical Oncology.
The findings from their ongoing phase II study are the first prospective results to demonstrate efficacy in this poor-prognosis population, the researchers wrote. Earlier results from the study were reported at the American Society of Hematology meeting.
The 54 patients in the study, 25 of them refractory to ibrutinib and 6 to idelalisib, received venetoclax 20 mg daily followed by a 5-week ramp up in dosage to 400 mg daily. Over half of the patients had received more than five prior therapies; 83% did not have IGHV mutations, 20% had absolute lymphocyte counts exceeding 100 x 109, 35% had 17p deletions, and 24% had at least one node that was 10 cm or larger.
Of the patients who had previously received ibrutinib, four discontinued venetoclax because of progressive disease and four others had respiratory failure, multiorgan failure, death of unknown cause, or consent withdrawal. Of those who previously received idelalisib, four halted therapy because of progressive disease and failure to respond. Of 48 evaluable patients, 38 previously received ibrutinib, and 10 previously received idelalisib.
The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib.
Grade 3/4 adverse events were seen in over 10% of patients and included neutropenia (39%), thrombocytopenia (22%), anemia (20%), leukopenia (13%), and pneumonia (13%). Significant adverse events seen in at least two patients included pneumonia (9%), febrile neutropenia (7%), increased potassium, multiorgan failure, and septic shock (4% each).
The study is sponsored by AbbVie.
FROM ASCO 2016
Key clinical point: Venetoclax can achieve responses in patients who are refractory to ibrutinib.
Major finding: The overall response rate was 61% (23 of 38 patients) for patients refractory to ibrutinib and 50% (5 of 10 patients) for those refractory to idelalisib. A complete response was seen in three patients, all refractory to ibrutinib..
Data source: Data on 54 patients in an ongoing phase II study.
Disclosures: The study is sponsored by AbbVie.
Why patients don’t report possible cancer symptoms
Photo courtesy of NIH
Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.
The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.
“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.
“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”
For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.
The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”
Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.
The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.
Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.
Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.
Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.
On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.
And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.
“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.
“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.” 
Photo courtesy of NIH
Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.
The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.
“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.
“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”
For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.
The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”
Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.
The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.
Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.
Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.
Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.
On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.
And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.
“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.
“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”
Photo courtesy of NIH
Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.
The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.
“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.
“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”
For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.
The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”
Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.
The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.
Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.
Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.
Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.
On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.
And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.
“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.
“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”
Team simplifies synthesis of anticancer agent
Photo courtesy of Jeff Fitlow
and Rice University
Researchers say they have streamlined synthesis of delta12-prostaglandin J3, a molecule that has been shown to kill leukemia cells.
Total synthesis of the molecule now requires only 6 steps from commercially available starting materials.
The researchers say this work sets the stage for large-scale synthesis of the molecule—a lipid found in nearly all animal tissues—and related compounds that can be produced as potential anticancer agents.
K.C. Nicolaou, PhD, of Rice University in Houston, Texas, and his colleagues described the work in Chemistry - A European Journal.
The prostaglandin the researchers synthesized had been isolated in 2011 as a secondary metabolite formed from eicosapentaenoic acid, which is found primarily in fish oil.
The team reported the first total synthesis of the molecule in 2014. That allowed them to confirm its structure.
Now, the researchers have established techniques to develop related disease-fighting compounds and ramp up bulk production if necessary.
Several such prostaglandin derivatives under consideration as preclinical drug candidates were detailed in a second paper published in the Journal of the American Chemical Society.
That publication described the synthesis of dozens of prostaglandin derivatives that were tested against a range of cancer cells by the National Cancer Institute.
One such derivative, macrolactone 11, is currently under evaluation as a preclinical drug candidate. Related compounds macrolactone 33 and 44 showed evidence of even higher potency against leukemia, lung cancer, colon cancer, melanoma, renal, and prostate cancer.
“The macrolactones are very good—better than the natural product—and now we’re following this lead to optimize the potency while minimizing toxicity,” Dr Nicolaou said. “It’s a balancing act.”
In addition, he and his colleagues are developing other drug candidates based on prostaglandin.
“In the process, we’ve developed a lot of nice chemistry, and we know a lot more about the biology of this compound,” Dr Nicolaou said. “We’ve advanced organic synthesis in general and also enriched the knowledge about how these kinds of molecules behave. We hope the papers provide some ideas and leads and inspiration for others to follow.”
Photo courtesy of Jeff Fitlow
and Rice University
Researchers say they have streamlined synthesis of delta12-prostaglandin J3, a molecule that has been shown to kill leukemia cells.
Total synthesis of the molecule now requires only 6 steps from commercially available starting materials.
The researchers say this work sets the stage for large-scale synthesis of the molecule—a lipid found in nearly all animal tissues—and related compounds that can be produced as potential anticancer agents.
K.C. Nicolaou, PhD, of Rice University in Houston, Texas, and his colleagues described the work in Chemistry - A European Journal.
The prostaglandin the researchers synthesized had been isolated in 2011 as a secondary metabolite formed from eicosapentaenoic acid, which is found primarily in fish oil.
The team reported the first total synthesis of the molecule in 2014. That allowed them to confirm its structure.
Now, the researchers have established techniques to develop related disease-fighting compounds and ramp up bulk production if necessary.
Several such prostaglandin derivatives under consideration as preclinical drug candidates were detailed in a second paper published in the Journal of the American Chemical Society.
That publication described the synthesis of dozens of prostaglandin derivatives that were tested against a range of cancer cells by the National Cancer Institute.
One such derivative, macrolactone 11, is currently under evaluation as a preclinical drug candidate. Related compounds macrolactone 33 and 44 showed evidence of even higher potency against leukemia, lung cancer, colon cancer, melanoma, renal, and prostate cancer.
“The macrolactones are very good—better than the natural product—and now we’re following this lead to optimize the potency while minimizing toxicity,” Dr Nicolaou said. “It’s a balancing act.”
In addition, he and his colleagues are developing other drug candidates based on prostaglandin.
“In the process, we’ve developed a lot of nice chemistry, and we know a lot more about the biology of this compound,” Dr Nicolaou said. “We’ve advanced organic synthesis in general and also enriched the knowledge about how these kinds of molecules behave. We hope the papers provide some ideas and leads and inspiration for others to follow.”
Photo courtesy of Jeff Fitlow
and Rice University
Researchers say they have streamlined synthesis of delta12-prostaglandin J3, a molecule that has been shown to kill leukemia cells.
Total synthesis of the molecule now requires only 6 steps from commercially available starting materials.
The researchers say this work sets the stage for large-scale synthesis of the molecule—a lipid found in nearly all animal tissues—and related compounds that can be produced as potential anticancer agents.
K.C. Nicolaou, PhD, of Rice University in Houston, Texas, and his colleagues described the work in Chemistry - A European Journal.
The prostaglandin the researchers synthesized had been isolated in 2011 as a secondary metabolite formed from eicosapentaenoic acid, which is found primarily in fish oil.
The team reported the first total synthesis of the molecule in 2014. That allowed them to confirm its structure.
Now, the researchers have established techniques to develop related disease-fighting compounds and ramp up bulk production if necessary.
Several such prostaglandin derivatives under consideration as preclinical drug candidates were detailed in a second paper published in the Journal of the American Chemical Society.
That publication described the synthesis of dozens of prostaglandin derivatives that were tested against a range of cancer cells by the National Cancer Institute.
One such derivative, macrolactone 11, is currently under evaluation as a preclinical drug candidate. Related compounds macrolactone 33 and 44 showed evidence of even higher potency against leukemia, lung cancer, colon cancer, melanoma, renal, and prostate cancer.
“The macrolactones are very good—better than the natural product—and now we’re following this lead to optimize the potency while minimizing toxicity,” Dr Nicolaou said. “It’s a balancing act.”
In addition, he and his colleagues are developing other drug candidates based on prostaglandin.
“In the process, we’ve developed a lot of nice chemistry, and we know a lot more about the biology of this compound,” Dr Nicolaou said. “We’ve advanced organic synthesis in general and also enriched the knowledge about how these kinds of molecules behave. We hope the papers provide some ideas and leads and inspiration for others to follow.”
Phototherapy may increase risk of pediatric cancers
phototherapy to treat
neonatal jaundice
Photo by Martin Pot
Two new studies raise questions about a possible link between childhood cancer and phototherapy for newborn jaundice.
One study showed a significant positive association between phototherapy and 2 cancer types—myeloid leukemia and kidney cancer—but the other study did not.
Although these results are inconclusive, researchers say clinicians should exercise caution in prescribing phototherapy for infants whose jaundice is likely to resolve on its own.
However, the findings should not discourage the use of phototherapy in infants who otherwise would be at risk of brain damage or hearing loss.
The studies were published in Pediatrics alongside a related editorial.
“Phototherapy has been perceived by most as causing minimal risk to the infant,” said editorial author A. Lindsay Frazier, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“Although these studies are inconclusive and do not prove a relationship between phototherapy and cancer, they should give us pause. That being said, however, the brain damage and hearing loss from high bilirubin levels are real and well-documented, and the suggested risk of cancer from these new studies is both unclear and very small.”
Kaiser Permanente study
Thomas B. Newman, MD, of University of California, San Francisco, and his colleagues conducted a study of children born in Kaiser Permanente Northern California hospitals from 1995 to 2011. The researchers analyzed data on 499,621 children born at 35 weeks’ gestation or later.
There were 60 cases of cancer among the 39,403 children exposed to phototherapy and 651 cases of cancer among the 460,218 children who were not exposed to phototherapy. That translates to 25 per 100,000 person-years and 18 per 100,000 person-years, respectively, for an incidence rate ratio (IRR) of 1.4 (P=0.01).
In an unadjusted analysis, phototherapy was associated with increased rates of any leukemia (IRR=2.1, P=0.0007), nonlymphocytic leukemia (IRR=4.0, P=0.0004), and liver cancer (IRR=5.2, P=0.04).
However, when the researchers adjusted for bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, these associations were no longer statistically significant.
Study of California hospitals
Andrea C. Wickremasinghe, MD, of Kaiser Permanente Northern California in Santa Clara, and her colleagues conducted a study of children born in California hospitals from 1998 to 2007.
The team analyzed data from the California Office of Statewide Health Planning and Development, which included 5,144,849 infants born at 35 weeks’ gestation or later.
There were 58 cases of cancer among the 178,017 infants exposed to phototherapy and 1042 cancer cases among the 4,966,832 infants who were not exposed to phototherapy. That translated to 32.6 per 100,000 and 21.0 per 100,000, respectively, for a relative risk of 1.6 (95% confidence interval [CI], 1.2–2.0; P=0.002).
In propensity-adjusted analyses, there were significant positive associations between phototherapy and overall cancer (adjusted odds ratio [aOR]=1.4; 95% CI, 1.1–1.9; P=0.007), myeloid leukemia (aOR=2.6; 95% CI, 1.3–5.0; P=0.005), and kidney cancer (aOR=2.5; 95% CI, 1.2–5.1; P=0.02).
Dr Frazier noted that these studies come at a time when the number of infants receiving phototherapy is increasing, perhaps because of the availability of light therapy units that can be used in the home. In the Kaiser Permanente study, 15.9% of infants received phototherapy in 2011, compared to 2.7% in 1995.
“What is concerning is the fact that, at least in the Kaiser Permanente Northern California healthcare system, the number of children receiving phototherapy has dramatically increased,” Dr Frazier said.
“The risks associated with such a prevalent exposure require close scrutiny. If I were the one prescribing phototherapy today, I would want to be sure it was indicated.”
phototherapy to treat
neonatal jaundice
Photo by Martin Pot
Two new studies raise questions about a possible link between childhood cancer and phototherapy for newborn jaundice.
One study showed a significant positive association between phototherapy and 2 cancer types—myeloid leukemia and kidney cancer—but the other study did not.
Although these results are inconclusive, researchers say clinicians should exercise caution in prescribing phototherapy for infants whose jaundice is likely to resolve on its own.
However, the findings should not discourage the use of phototherapy in infants who otherwise would be at risk of brain damage or hearing loss.
The studies were published in Pediatrics alongside a related editorial.
“Phototherapy has been perceived by most as causing minimal risk to the infant,” said editorial author A. Lindsay Frazier, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“Although these studies are inconclusive and do not prove a relationship between phototherapy and cancer, they should give us pause. That being said, however, the brain damage and hearing loss from high bilirubin levels are real and well-documented, and the suggested risk of cancer from these new studies is both unclear and very small.”
Kaiser Permanente study
Thomas B. Newman, MD, of University of California, San Francisco, and his colleagues conducted a study of children born in Kaiser Permanente Northern California hospitals from 1995 to 2011. The researchers analyzed data on 499,621 children born at 35 weeks’ gestation or later.
There were 60 cases of cancer among the 39,403 children exposed to phototherapy and 651 cases of cancer among the 460,218 children who were not exposed to phototherapy. That translates to 25 per 100,000 person-years and 18 per 100,000 person-years, respectively, for an incidence rate ratio (IRR) of 1.4 (P=0.01).
In an unadjusted analysis, phototherapy was associated with increased rates of any leukemia (IRR=2.1, P=0.0007), nonlymphocytic leukemia (IRR=4.0, P=0.0004), and liver cancer (IRR=5.2, P=0.04).
However, when the researchers adjusted for bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, these associations were no longer statistically significant.
Study of California hospitals
Andrea C. Wickremasinghe, MD, of Kaiser Permanente Northern California in Santa Clara, and her colleagues conducted a study of children born in California hospitals from 1998 to 2007.
The team analyzed data from the California Office of Statewide Health Planning and Development, which included 5,144,849 infants born at 35 weeks’ gestation or later.
There were 58 cases of cancer among the 178,017 infants exposed to phototherapy and 1042 cancer cases among the 4,966,832 infants who were not exposed to phototherapy. That translated to 32.6 per 100,000 and 21.0 per 100,000, respectively, for a relative risk of 1.6 (95% confidence interval [CI], 1.2–2.0; P=0.002).
In propensity-adjusted analyses, there were significant positive associations between phototherapy and overall cancer (adjusted odds ratio [aOR]=1.4; 95% CI, 1.1–1.9; P=0.007), myeloid leukemia (aOR=2.6; 95% CI, 1.3–5.0; P=0.005), and kidney cancer (aOR=2.5; 95% CI, 1.2–5.1; P=0.02).
Dr Frazier noted that these studies come at a time when the number of infants receiving phototherapy is increasing, perhaps because of the availability of light therapy units that can be used in the home. In the Kaiser Permanente study, 15.9% of infants received phototherapy in 2011, compared to 2.7% in 1995.
“What is concerning is the fact that, at least in the Kaiser Permanente Northern California healthcare system, the number of children receiving phototherapy has dramatically increased,” Dr Frazier said.
“The risks associated with such a prevalent exposure require close scrutiny. If I were the one prescribing phototherapy today, I would want to be sure it was indicated.”
phototherapy to treat
neonatal jaundice
Photo by Martin Pot
Two new studies raise questions about a possible link between childhood cancer and phototherapy for newborn jaundice.
One study showed a significant positive association between phototherapy and 2 cancer types—myeloid leukemia and kidney cancer—but the other study did not.
Although these results are inconclusive, researchers say clinicians should exercise caution in prescribing phototherapy for infants whose jaundice is likely to resolve on its own.
However, the findings should not discourage the use of phototherapy in infants who otherwise would be at risk of brain damage or hearing loss.
The studies were published in Pediatrics alongside a related editorial.
“Phototherapy has been perceived by most as causing minimal risk to the infant,” said editorial author A. Lindsay Frazier, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“Although these studies are inconclusive and do not prove a relationship between phototherapy and cancer, they should give us pause. That being said, however, the brain damage and hearing loss from high bilirubin levels are real and well-documented, and the suggested risk of cancer from these new studies is both unclear and very small.”
Kaiser Permanente study
Thomas B. Newman, MD, of University of California, San Francisco, and his colleagues conducted a study of children born in Kaiser Permanente Northern California hospitals from 1995 to 2011. The researchers analyzed data on 499,621 children born at 35 weeks’ gestation or later.
There were 60 cases of cancer among the 39,403 children exposed to phototherapy and 651 cases of cancer among the 460,218 children who were not exposed to phototherapy. That translates to 25 per 100,000 person-years and 18 per 100,000 person-years, respectively, for an incidence rate ratio (IRR) of 1.4 (P=0.01).
In an unadjusted analysis, phototherapy was associated with increased rates of any leukemia (IRR=2.1, P=0.0007), nonlymphocytic leukemia (IRR=4.0, P=0.0004), and liver cancer (IRR=5.2, P=0.04).
However, when the researchers adjusted for bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, these associations were no longer statistically significant.
Study of California hospitals
Andrea C. Wickremasinghe, MD, of Kaiser Permanente Northern California in Santa Clara, and her colleagues conducted a study of children born in California hospitals from 1998 to 2007.
The team analyzed data from the California Office of Statewide Health Planning and Development, which included 5,144,849 infants born at 35 weeks’ gestation or later.
There were 58 cases of cancer among the 178,017 infants exposed to phototherapy and 1042 cancer cases among the 4,966,832 infants who were not exposed to phototherapy. That translated to 32.6 per 100,000 and 21.0 per 100,000, respectively, for a relative risk of 1.6 (95% confidence interval [CI], 1.2–2.0; P=0.002).
In propensity-adjusted analyses, there were significant positive associations between phototherapy and overall cancer (adjusted odds ratio [aOR]=1.4; 95% CI, 1.1–1.9; P=0.007), myeloid leukemia (aOR=2.6; 95% CI, 1.3–5.0; P=0.005), and kidney cancer (aOR=2.5; 95% CI, 1.2–5.1; P=0.02).
Dr Frazier noted that these studies come at a time when the number of infants receiving phototherapy is increasing, perhaps because of the availability of light therapy units that can be used in the home. In the Kaiser Permanente study, 15.9% of infants received phototherapy in 2011, compared to 2.7% in 1995.
“What is concerning is the fact that, at least in the Kaiser Permanente Northern California healthcare system, the number of children receiving phototherapy has dramatically increased,” Dr Frazier said.
“The risks associated with such a prevalent exposure require close scrutiny. If I were the one prescribing phototherapy today, I would want to be sure it was indicated.”
Dasatinib bests imatinib on molecular, cytogenic response rates in CML
Overall survival and progression-free survival were similar at 5 years in chronic myeloid leukemia patients receiving dasatinib or imatinib, but those given dasatinib had higher major molecular response rates and complete cytogenic response rates without a higher rate of adverse events, based on an extension study of previously published data from the DASISION trial.
The DASISION phase III clinical trial included 519 patients with newly diagnosed and treatment-naive chronic myeloid leukemia. Participants were randomly assigned to receive either 100 mg of dasatinib daily (259 patients) or 400 mg of imatinib daily (260 patients). Dosage was altered on a per-patient basis if adverse events or suboptimal responses were observed. The median average daily dose was 99 mg for dasatinib and 400 mg for imatinib after 5 years.
“Initial results showed that dasatinib had met its primary end point of superior efficacy compared with imatinib and had an acceptable safety profile, leading to its approval for first-line use,” reported Dr. Jorge Cortes of the University of Texas MD Anderson Cancer Center, Houston, and his associates (J Clin Oncol. 2016 May 23. doi: 10.1200/JCO.2015.64.8899). Given the faster and deeper molecular responses seen in patients taking dasatinib, “dasatinib should continue to be considered a standard first-line therapy for patients with newly diagnosed” chronic myeloid leukemia, they wrote.
In DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients), complete cytogenic response, major molecular response, overall survival, and progression-free survival were measured.
The major molecular response rate was significantly higher for patients receiving dasatinib, compared with patients receiving imatinib (76% vs. 64%, P = .0022).
The rate of complete cytogenic response was 28% for dasatinib and 26% for imatinib.
The 5-year overall survival for patients receiving dasatinib was 91% and was not significantly different than the overall survival rate for patients receiving imatinib (90%, P = .1192). Five-year progression-free survival was 85% for patients receiving dasatinib and 86% for patients receiving imatinib.
Grade 3 or 4 adverse events were seen in 15% of patients receiving dasatinib and 11% of patients receiving imatinib. After 5 years, 26 patients had died in each experimental group.
This study was supported by Bristol-Myers Squibb. Eleven investigators reported serving in advisory roles or receiving financial compensation from multiple companies. One investigator had no disclosures to report.
On Twitter @JessCraig_OP
Overall survival and progression-free survival were similar at 5 years in chronic myeloid leukemia patients receiving dasatinib or imatinib, but those given dasatinib had higher major molecular response rates and complete cytogenic response rates without a higher rate of adverse events, based on an extension study of previously published data from the DASISION trial.
The DASISION phase III clinical trial included 519 patients with newly diagnosed and treatment-naive chronic myeloid leukemia. Participants were randomly assigned to receive either 100 mg of dasatinib daily (259 patients) or 400 mg of imatinib daily (260 patients). Dosage was altered on a per-patient basis if adverse events or suboptimal responses were observed. The median average daily dose was 99 mg for dasatinib and 400 mg for imatinib after 5 years.
“Initial results showed that dasatinib had met its primary end point of superior efficacy compared with imatinib and had an acceptable safety profile, leading to its approval for first-line use,” reported Dr. Jorge Cortes of the University of Texas MD Anderson Cancer Center, Houston, and his associates (J Clin Oncol. 2016 May 23. doi: 10.1200/JCO.2015.64.8899). Given the faster and deeper molecular responses seen in patients taking dasatinib, “dasatinib should continue to be considered a standard first-line therapy for patients with newly diagnosed” chronic myeloid leukemia, they wrote.
In DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients), complete cytogenic response, major molecular response, overall survival, and progression-free survival were measured.
The major molecular response rate was significantly higher for patients receiving dasatinib, compared with patients receiving imatinib (76% vs. 64%, P = .0022).
The rate of complete cytogenic response was 28% for dasatinib and 26% for imatinib.
The 5-year overall survival for patients receiving dasatinib was 91% and was not significantly different than the overall survival rate for patients receiving imatinib (90%, P = .1192). Five-year progression-free survival was 85% for patients receiving dasatinib and 86% for patients receiving imatinib.
Grade 3 or 4 adverse events were seen in 15% of patients receiving dasatinib and 11% of patients receiving imatinib. After 5 years, 26 patients had died in each experimental group.
This study was supported by Bristol-Myers Squibb. Eleven investigators reported serving in advisory roles or receiving financial compensation from multiple companies. One investigator had no disclosures to report.
On Twitter @JessCraig_OP
Overall survival and progression-free survival were similar at 5 years in chronic myeloid leukemia patients receiving dasatinib or imatinib, but those given dasatinib had higher major molecular response rates and complete cytogenic response rates without a higher rate of adverse events, based on an extension study of previously published data from the DASISION trial.
The DASISION phase III clinical trial included 519 patients with newly diagnosed and treatment-naive chronic myeloid leukemia. Participants were randomly assigned to receive either 100 mg of dasatinib daily (259 patients) or 400 mg of imatinib daily (260 patients). Dosage was altered on a per-patient basis if adverse events or suboptimal responses were observed. The median average daily dose was 99 mg for dasatinib and 400 mg for imatinib after 5 years.
“Initial results showed that dasatinib had met its primary end point of superior efficacy compared with imatinib and had an acceptable safety profile, leading to its approval for first-line use,” reported Dr. Jorge Cortes of the University of Texas MD Anderson Cancer Center, Houston, and his associates (J Clin Oncol. 2016 May 23. doi: 10.1200/JCO.2015.64.8899). Given the faster and deeper molecular responses seen in patients taking dasatinib, “dasatinib should continue to be considered a standard first-line therapy for patients with newly diagnosed” chronic myeloid leukemia, they wrote.
In DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients), complete cytogenic response, major molecular response, overall survival, and progression-free survival were measured.
The major molecular response rate was significantly higher for patients receiving dasatinib, compared with patients receiving imatinib (76% vs. 64%, P = .0022).
The rate of complete cytogenic response was 28% for dasatinib and 26% for imatinib.
The 5-year overall survival for patients receiving dasatinib was 91% and was not significantly different than the overall survival rate for patients receiving imatinib (90%, P = .1192). Five-year progression-free survival was 85% for patients receiving dasatinib and 86% for patients receiving imatinib.
Grade 3 or 4 adverse events were seen in 15% of patients receiving dasatinib and 11% of patients receiving imatinib. After 5 years, 26 patients had died in each experimental group.
This study was supported by Bristol-Myers Squibb. Eleven investigators reported serving in advisory roles or receiving financial compensation from multiple companies. One investigator had no disclosures to report.
On Twitter @JessCraig_OP
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Patients with chronic myeloid leukemia who received dasatinib experienced higher rates of major molecular response and cytogenic response than did patients treated with imatinib. The improvement in response rate did not come with significantly more adverse events.
Major finding: The major molecular response rate was significantly higher at 76% for patients receiving dasatinib, compared with 64% for patients receiving imatinib (P = .0022).
Data source: A multinational, open-label, phase III trial of 519 patients with treatment-naive myeloid leukemia.
Disclosures: This study was supported by Bristol-Myers Squibb. Eleven investigators reported serving in advisory roles or receiving financial compensation from multiple companies. One investigator had no disclosures to report.
Study reveals how BET inhibitors kill cancer cells
Image courtesy of PNAS
Researchers say they have determined how BET inhibitors fight hematologic malignancies.
Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.
The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.
The findings have been published in Leukaemia.
Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).
The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.
“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”
The researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.
These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.
“Understanding how the drugs work gives us the opportunity to investigate new treatments—for example, by using combination therapies or altering the dosage and timing of treatment to prevent drug resistance from emerging,” Dr Glaser said.
Image courtesy of PNAS
Researchers say they have determined how BET inhibitors fight hematologic malignancies.
Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.
The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.
The findings have been published in Leukaemia.
Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).
The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.
“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”
The researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.
These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.
“Understanding how the drugs work gives us the opportunity to investigate new treatments—for example, by using combination therapies or altering the dosage and timing of treatment to prevent drug resistance from emerging,” Dr Glaser said.
Image courtesy of PNAS
Researchers say they have determined how BET inhibitors fight hematologic malignancies.
Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.
The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.
The findings have been published in Leukaemia.
Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).
The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.
“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”
The researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.
These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.
“Understanding how the drugs work gives us the opportunity to investigate new treatments—for example, by using combination therapies or altering the dosage and timing of treatment to prevent drug resistance from emerging,” Dr Glaser said.
Fertility concerns of female cancer survivors
Photo by Vera Kratochvil
A new study indicates that many young adult female cancer survivors do not receive adequate information about their fertility as part of their survivorship care, despite having concerns about their ability to bear children in the future.
The research, published in Cancer, suggests a need for better resources to support cancer survivors in making informed decisions about their reproductive options after they complete treatment.
To conduct this study, Catherine Benedict, PhD, of North Shore-Long Island Jewish Medical Center in Manhasset, New York, and her colleagues asked female cancer survivors to complete a web-based, anonymous survey.
There were 346 participants. They had an average age of 29.9 and had completed treatment an average of 4.9 years earlier.
The investigators focused on a subgroup of 179 women with uncertain fertility status who had not previously undergone or attempted fertility preservation, either before or after their cancer treatment, and who either wanted future children or were unsure.
Many of these women said they did not have enough information concerning their risk of infertility (58%), risk of early menopause (60%), options to assess their fertility (62%), options to preserve their fertility (51%), or options for alternative family building (43%).
The women’s greatest reproductive concerns were potential fertility problems and the health of a future child. Sixty-four percent of the women said they were concerned about not being able to have children (or more children), and 59% were worried about passing the risk of cancer on to their future children.
Only 13% of women said they were well informed about options for preserving fertility, and 74% were unclear about their personal values regarding fertility preservation.
Seventy percent of the women said they hadn’t received enough advice on fertility preservation, and 35% said they didn’t have enough support to make a decision about fertility preservation.
The investigators found a significant association between greater unmet information needs and higher levels of decisional conflict about fertility preservation (P<0.001).
On the other hand, having undergone a fertility evaluation after treatment was associated with lower decisional conflict (P=0.02).
The investigators said these findings establish the need for support services to help young female cancer survivors make decisions about fertility preservation and family-building as part of survivorship care.
The literature has largely focused on the clinical and support needs of women making fertility decisions before their treatment begins, but most patients do not preserve their fertility before treatment for a number of reasons, despite wanting children in the future.
“The potential loss of fertility has been described in the literature as being almost as painful, if not more so, than the cancer diagnosis itself,” Dr Benedict said.
“Failure to provide information and address concerns with respect to fertility-related decisions may have lasting consequences for young women who hope to move on from their cancer experience to achieve important life goals such as having children. For women at risk for early menopause, delaying fertility-related decisions may cause them to miss their narrowed window of opportunity to preserve their fertility, if desired.”
Photo by Vera Kratochvil
A new study indicates that many young adult female cancer survivors do not receive adequate information about their fertility as part of their survivorship care, despite having concerns about their ability to bear children in the future.
The research, published in Cancer, suggests a need for better resources to support cancer survivors in making informed decisions about their reproductive options after they complete treatment.
To conduct this study, Catherine Benedict, PhD, of North Shore-Long Island Jewish Medical Center in Manhasset, New York, and her colleagues asked female cancer survivors to complete a web-based, anonymous survey.
There were 346 participants. They had an average age of 29.9 and had completed treatment an average of 4.9 years earlier.
The investigators focused on a subgroup of 179 women with uncertain fertility status who had not previously undergone or attempted fertility preservation, either before or after their cancer treatment, and who either wanted future children or were unsure.
Many of these women said they did not have enough information concerning their risk of infertility (58%), risk of early menopause (60%), options to assess their fertility (62%), options to preserve their fertility (51%), or options for alternative family building (43%).
The women’s greatest reproductive concerns were potential fertility problems and the health of a future child. Sixty-four percent of the women said they were concerned about not being able to have children (or more children), and 59% were worried about passing the risk of cancer on to their future children.
Only 13% of women said they were well informed about options for preserving fertility, and 74% were unclear about their personal values regarding fertility preservation.
Seventy percent of the women said they hadn’t received enough advice on fertility preservation, and 35% said they didn’t have enough support to make a decision about fertility preservation.
The investigators found a significant association between greater unmet information needs and higher levels of decisional conflict about fertility preservation (P<0.001).
On the other hand, having undergone a fertility evaluation after treatment was associated with lower decisional conflict (P=0.02).
The investigators said these findings establish the need for support services to help young female cancer survivors make decisions about fertility preservation and family-building as part of survivorship care.
The literature has largely focused on the clinical and support needs of women making fertility decisions before their treatment begins, but most patients do not preserve their fertility before treatment for a number of reasons, despite wanting children in the future.
“The potential loss of fertility has been described in the literature as being almost as painful, if not more so, than the cancer diagnosis itself,” Dr Benedict said.
“Failure to provide information and address concerns with respect to fertility-related decisions may have lasting consequences for young women who hope to move on from their cancer experience to achieve important life goals such as having children. For women at risk for early menopause, delaying fertility-related decisions may cause them to miss their narrowed window of opportunity to preserve their fertility, if desired.”
Photo by Vera Kratochvil
A new study indicates that many young adult female cancer survivors do not receive adequate information about their fertility as part of their survivorship care, despite having concerns about their ability to bear children in the future.
The research, published in Cancer, suggests a need for better resources to support cancer survivors in making informed decisions about their reproductive options after they complete treatment.
To conduct this study, Catherine Benedict, PhD, of North Shore-Long Island Jewish Medical Center in Manhasset, New York, and her colleagues asked female cancer survivors to complete a web-based, anonymous survey.
There were 346 participants. They had an average age of 29.9 and had completed treatment an average of 4.9 years earlier.
The investigators focused on a subgroup of 179 women with uncertain fertility status who had not previously undergone or attempted fertility preservation, either before or after their cancer treatment, and who either wanted future children or were unsure.
Many of these women said they did not have enough information concerning their risk of infertility (58%), risk of early menopause (60%), options to assess their fertility (62%), options to preserve their fertility (51%), or options for alternative family building (43%).
The women’s greatest reproductive concerns were potential fertility problems and the health of a future child. Sixty-four percent of the women said they were concerned about not being able to have children (or more children), and 59% were worried about passing the risk of cancer on to their future children.
Only 13% of women said they were well informed about options for preserving fertility, and 74% were unclear about their personal values regarding fertility preservation.
Seventy percent of the women said they hadn’t received enough advice on fertility preservation, and 35% said they didn’t have enough support to make a decision about fertility preservation.
The investigators found a significant association between greater unmet information needs and higher levels of decisional conflict about fertility preservation (P<0.001).
On the other hand, having undergone a fertility evaluation after treatment was associated with lower decisional conflict (P=0.02).
The investigators said these findings establish the need for support services to help young female cancer survivors make decisions about fertility preservation and family-building as part of survivorship care.
The literature has largely focused on the clinical and support needs of women making fertility decisions before their treatment begins, but most patients do not preserve their fertility before treatment for a number of reasons, despite wanting children in the future.
“The potential loss of fertility has been described in the literature as being almost as painful, if not more so, than the cancer diagnosis itself,” Dr Benedict said.
“Failure to provide information and address concerns with respect to fertility-related decisions may have lasting consequences for young women who hope to move on from their cancer experience to achieve important life goals such as having children. For women at risk for early menopause, delaying fertility-related decisions may cause them to miss their narrowed window of opportunity to preserve their fertility, if desired.”
Cognitive impairment in ALL survivors
Photo by Bill Branson
New research indicates that survivors of pediatric acute lymphoblastic leukemia (ALL) suffer from brain injury even if they have no history of central nervous system disease or cranial radiation.
The study suggests the neurotoxic effects of chemotherapeutic drugs on the developing brains of young ALL patients may impair their cognitive functioning by disrupting the formation of neural networks that connect brain regions and transfer information.
Shelli Kesler, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these findings in Brain Connectivity.
The researchers used diffusion tensor imaging to analyze and compare the gray matter connectome of 31 pediatric ALL survivors and 39 matched control subjects.
The team found significantly greater cognitive impairment among the ALL survivors (P=0.027), as well as significantly lower connectivity, based on small-worldness (P=0.007) and network clustering coefficient (P=0.019).
The researchers noted that clustered connectivity was altered in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions in the ALL survivors.
The team also described a model that can be used to predict cognitive impairment in ALL survivors. The model’s classification accuracy was 89.39% (P<0.0001), its sensitivity was 95.83%, and specificity was 85.71%.
“As survival rates for cancer patients increase, issues related to survivorship, such as chemotherapy-induced cognitive impairment, become more important to the cancer research community,” said Christopher Pawela, PhD, co-editor-in-chief of Brain Connectivity and an assistant professor at the Medical College of Wisconsin in Milwaukee.
“Dr Kesler and colleagues are developing new MRI-based biomarkers to measure brain changes associated with the neurotoxic effects of chemotherapy in the brain. These biomarkers may find utility in providing insight into the mechanisms of brain damage caused by chemotherapeutic drugs and could be used to develop neuroprotective therapies to mitigate the harmful effects of these drugs on the brain.”
Photo by Bill Branson
New research indicates that survivors of pediatric acute lymphoblastic leukemia (ALL) suffer from brain injury even if they have no history of central nervous system disease or cranial radiation.
The study suggests the neurotoxic effects of chemotherapeutic drugs on the developing brains of young ALL patients may impair their cognitive functioning by disrupting the formation of neural networks that connect brain regions and transfer information.
Shelli Kesler, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these findings in Brain Connectivity.
The researchers used diffusion tensor imaging to analyze and compare the gray matter connectome of 31 pediatric ALL survivors and 39 matched control subjects.
The team found significantly greater cognitive impairment among the ALL survivors (P=0.027), as well as significantly lower connectivity, based on small-worldness (P=0.007) and network clustering coefficient (P=0.019).
The researchers noted that clustered connectivity was altered in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions in the ALL survivors.
The team also described a model that can be used to predict cognitive impairment in ALL survivors. The model’s classification accuracy was 89.39% (P<0.0001), its sensitivity was 95.83%, and specificity was 85.71%.
“As survival rates for cancer patients increase, issues related to survivorship, such as chemotherapy-induced cognitive impairment, become more important to the cancer research community,” said Christopher Pawela, PhD, co-editor-in-chief of Brain Connectivity and an assistant professor at the Medical College of Wisconsin in Milwaukee.
“Dr Kesler and colleagues are developing new MRI-based biomarkers to measure brain changes associated with the neurotoxic effects of chemotherapy in the brain. These biomarkers may find utility in providing insight into the mechanisms of brain damage caused by chemotherapeutic drugs and could be used to develop neuroprotective therapies to mitigate the harmful effects of these drugs on the brain.”
Photo by Bill Branson
New research indicates that survivors of pediatric acute lymphoblastic leukemia (ALL) suffer from brain injury even if they have no history of central nervous system disease or cranial radiation.
The study suggests the neurotoxic effects of chemotherapeutic drugs on the developing brains of young ALL patients may impair their cognitive functioning by disrupting the formation of neural networks that connect brain regions and transfer information.
Shelli Kesler, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these findings in Brain Connectivity.
The researchers used diffusion tensor imaging to analyze and compare the gray matter connectome of 31 pediatric ALL survivors and 39 matched control subjects.
The team found significantly greater cognitive impairment among the ALL survivors (P=0.027), as well as significantly lower connectivity, based on small-worldness (P=0.007) and network clustering coefficient (P=0.019).
The researchers noted that clustered connectivity was altered in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions in the ALL survivors.
The team also described a model that can be used to predict cognitive impairment in ALL survivors. The model’s classification accuracy was 89.39% (P<0.0001), its sensitivity was 95.83%, and specificity was 85.71%.
“As survival rates for cancer patients increase, issues related to survivorship, such as chemotherapy-induced cognitive impairment, become more important to the cancer research community,” said Christopher Pawela, PhD, co-editor-in-chief of Brain Connectivity and an assistant professor at the Medical College of Wisconsin in Milwaukee.
“Dr Kesler and colleagues are developing new MRI-based biomarkers to measure brain changes associated with the neurotoxic effects of chemotherapy in the brain. These biomarkers may find utility in providing insight into the mechanisms of brain damage caused by chemotherapeutic drugs and could be used to develop neuroprotective therapies to mitigate the harmful effects of these drugs on the brain.”
Drug granted breakthrough designation for AML
Image by Lance Liotta
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for CPX-351 (Vyxeos), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle, to treat adults with therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Phase 3 trial
The breakthrough designation for CPX-351 is primarily based on positive results from a phase 3 trial in older patients with previously untreated, high-risk, secondary AML.
The trial was sponsored by Celator Pharmaceuticals, Inc., the company developing CPX-351.
The company has released some results from the trial, and additional data are scheduled to be presented at the 2016 ASCO Annual Meeting (abstract 7000).
The trial enrolled 309 patients, ages 60 to 75, with one of the following:
- Untreated AML and a history of prior cytotoxic treatment
- Antecedent myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia, with or without prior hypomethylating therapy
- AML with WHO-defined, MDS-related cytogenetic abnormalities.
One hundred and fifty-three patients were randomized to receive CPX-351, and 156 were randomized to 7+3 (cytarabine continuously for 7 days and a single dose of daunorubicin for the first 3 days).
The treatment arms were well-balanced for sex, race, age, performance status, AML subtype, MDS-related cytogenetics, and prior hypomethylating therapy.
The trial met its primary endpoint, demonstrating a significant improvement in overall survival with CPX-351. The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm. The hazard ratio was 0.69 (P=0.005).
According to researchers, there was no substantial difference between the treatment arms with regard to grade 3-5 adverse events.
About CPX-351
CPX-351 is a liposomal formulation of a 5:1 molar ratio of cytarabine and daunorubicin.
In one phase 2 trial, CPX-351 conferred a significant improvement in survival—over investigator’s choice of therapy—when used as salvage therapy in poor-risk patients with AML.
In another phase 2 trial, CPX-351 conferred a significant survival benefit—over 7+3—in patients with secondary AML.
The FDA previously granted CPX-351 fast track designation to treat elderly patients with secondary AML. The agency established the fast track designation process to expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.
The designation allows a drug’s developer to submit sections of a new drug application (NDA) on a rolling basis, so the FDA can review portions of the NDA as they are received instead of waiting for the entire NDA submission. A fast-track-designated product could be eligible for priority review if supported by clinical data at the time of NDA submission.
Image by Lance Liotta
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for CPX-351 (Vyxeos), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle, to treat adults with therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Phase 3 trial
The breakthrough designation for CPX-351 is primarily based on positive results from a phase 3 trial in older patients with previously untreated, high-risk, secondary AML.
The trial was sponsored by Celator Pharmaceuticals, Inc., the company developing CPX-351.
The company has released some results from the trial, and additional data are scheduled to be presented at the 2016 ASCO Annual Meeting (abstract 7000).
The trial enrolled 309 patients, ages 60 to 75, with one of the following:
- Untreated AML and a history of prior cytotoxic treatment
- Antecedent myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia, with or without prior hypomethylating therapy
- AML with WHO-defined, MDS-related cytogenetic abnormalities.
One hundred and fifty-three patients were randomized to receive CPX-351, and 156 were randomized to 7+3 (cytarabine continuously for 7 days and a single dose of daunorubicin for the first 3 days).
The treatment arms were well-balanced for sex, race, age, performance status, AML subtype, MDS-related cytogenetics, and prior hypomethylating therapy.
The trial met its primary endpoint, demonstrating a significant improvement in overall survival with CPX-351. The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm. The hazard ratio was 0.69 (P=0.005).
According to researchers, there was no substantial difference between the treatment arms with regard to grade 3-5 adverse events.
About CPX-351
CPX-351 is a liposomal formulation of a 5:1 molar ratio of cytarabine and daunorubicin.
In one phase 2 trial, CPX-351 conferred a significant improvement in survival—over investigator’s choice of therapy—when used as salvage therapy in poor-risk patients with AML.
In another phase 2 trial, CPX-351 conferred a significant survival benefit—over 7+3—in patients with secondary AML.
The FDA previously granted CPX-351 fast track designation to treat elderly patients with secondary AML. The agency established the fast track designation process to expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.
The designation allows a drug’s developer to submit sections of a new drug application (NDA) on a rolling basis, so the FDA can review portions of the NDA as they are received instead of waiting for the entire NDA submission. A fast-track-designated product could be eligible for priority review if supported by clinical data at the time of NDA submission.
Image by Lance Liotta
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for CPX-351 (Vyxeos), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle, to treat adults with therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Phase 3 trial
The breakthrough designation for CPX-351 is primarily based on positive results from a phase 3 trial in older patients with previously untreated, high-risk, secondary AML.
The trial was sponsored by Celator Pharmaceuticals, Inc., the company developing CPX-351.
The company has released some results from the trial, and additional data are scheduled to be presented at the 2016 ASCO Annual Meeting (abstract 7000).
The trial enrolled 309 patients, ages 60 to 75, with one of the following:
- Untreated AML and a history of prior cytotoxic treatment
- Antecedent myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia, with or without prior hypomethylating therapy
- AML with WHO-defined, MDS-related cytogenetic abnormalities.
One hundred and fifty-three patients were randomized to receive CPX-351, and 156 were randomized to 7+3 (cytarabine continuously for 7 days and a single dose of daunorubicin for the first 3 days).
The treatment arms were well-balanced for sex, race, age, performance status, AML subtype, MDS-related cytogenetics, and prior hypomethylating therapy.
The trial met its primary endpoint, demonstrating a significant improvement in overall survival with CPX-351. The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm. The hazard ratio was 0.69 (P=0.005).
According to researchers, there was no substantial difference between the treatment arms with regard to grade 3-5 adverse events.
About CPX-351
CPX-351 is a liposomal formulation of a 5:1 molar ratio of cytarabine and daunorubicin.
In one phase 2 trial, CPX-351 conferred a significant improvement in survival—over investigator’s choice of therapy—when used as salvage therapy in poor-risk patients with AML.
In another phase 2 trial, CPX-351 conferred a significant survival benefit—over 7+3—in patients with secondary AML.
The FDA previously granted CPX-351 fast track designation to treat elderly patients with secondary AML. The agency established the fast track designation process to expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.
The designation allows a drug’s developer to submit sections of a new drug application (NDA) on a rolling basis, so the FDA can review portions of the NDA as they are received instead of waiting for the entire NDA submission. A fast-track-designated product could be eligible for priority review if supported by clinical data at the time of NDA submission.