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Pathway appears key to fighting adenovirus
Using an animal model they developed, researchers have identified a pathway that inhibits replication of the adenovirus.
The team generated a new strain of Syrian hamster, a model in which human adenovirus replicates and causes illness similar to that observed in humans.
Experiments with this model suggested the Type I interferon pathway plays a key role in inhibiting adenovirus replication.
“[L]ike many other viruses, adenovirus can replicate at will when a patient’s immune system is suppressed,” said William Wold, PhD, of Saint Louis University in Missouri.
“Adenovirus can become very dangerous, such as for a child who is undergoing a bone marrow transplant to treat leukemia.”
Previously, Dr Wold led a research team that identified the Syrian hamster as an appropriate animal model to study adenovirus because species C human adenoviruses replicate in these animals.
For the current study, which was published in PLOS Pathogens, Dr Wold and his colleagues conducted experiments with a new Syrian hamster strain. In these animals, the STAT2 gene was functionally knocked out by site-specific gene targeting.
The researchers found that STAT2-knockout hamsters were extremely sensitive to infection with type 5 human adenovirus (Ad5).
The team infected both STAT2-knockout hamsters and wild-type controls with Ad5. Knockout hamsters had 100 to 1000 times the viral load of controls.
The knockout hamsters also had pathology characteristic of advanced adenovirus infection—yellow, mottled livers and enlarged gall bladders—whereas controls did not.
The adaptive immune response to Ad5 remained intact in the STAT2-knockout hamsters, as surviving animals were able to clear the virus.
However, the Type 1 interferon response was hampered in these animals. Knocking out STAT2 disrupted the Type 1 interferon pathway by interrupting the cascade of cell signaling.
The researchers said their findings suggest the disrupted Type I interferon pathway contributed to the increased Ad5 replication in the STAT2-knockout hamsters.
“Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model,” Dr Wold said. “The STAT2-knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola, hanta, and dengue viruses.”
The model was created by Zhongde Wang, PhD, and his colleagues at Utah State University in Logan, Utah. Dr Wang’s lab is the first to develop gene-targeting technologies in the Syrian hamster.
“The success we achieved in conducting gene-targeting in the Syrian hamster has provided the opportunity to create models for many of the human diseases for which there are either no existent animal models or severe limitations in the available animal models,” Dr Wang said. 
Using an animal model they developed, researchers have identified a pathway that inhibits replication of the adenovirus.
The team generated a new strain of Syrian hamster, a model in which human adenovirus replicates and causes illness similar to that observed in humans.
Experiments with this model suggested the Type I interferon pathway plays a key role in inhibiting adenovirus replication.
“[L]ike many other viruses, adenovirus can replicate at will when a patient’s immune system is suppressed,” said William Wold, PhD, of Saint Louis University in Missouri.
“Adenovirus can become very dangerous, such as for a child who is undergoing a bone marrow transplant to treat leukemia.”
Previously, Dr Wold led a research team that identified the Syrian hamster as an appropriate animal model to study adenovirus because species C human adenoviruses replicate in these animals.
For the current study, which was published in PLOS Pathogens, Dr Wold and his colleagues conducted experiments with a new Syrian hamster strain. In these animals, the STAT2 gene was functionally knocked out by site-specific gene targeting.
The researchers found that STAT2-knockout hamsters were extremely sensitive to infection with type 5 human adenovirus (Ad5).
The team infected both STAT2-knockout hamsters and wild-type controls with Ad5. Knockout hamsters had 100 to 1000 times the viral load of controls.
The knockout hamsters also had pathology characteristic of advanced adenovirus infection—yellow, mottled livers and enlarged gall bladders—whereas controls did not.
The adaptive immune response to Ad5 remained intact in the STAT2-knockout hamsters, as surviving animals were able to clear the virus.
However, the Type 1 interferon response was hampered in these animals. Knocking out STAT2 disrupted the Type 1 interferon pathway by interrupting the cascade of cell signaling.
The researchers said their findings suggest the disrupted Type I interferon pathway contributed to the increased Ad5 replication in the STAT2-knockout hamsters.
“Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model,” Dr Wold said. “The STAT2-knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola, hanta, and dengue viruses.”
The model was created by Zhongde Wang, PhD, and his colleagues at Utah State University in Logan, Utah. Dr Wang’s lab is the first to develop gene-targeting technologies in the Syrian hamster.
“The success we achieved in conducting gene-targeting in the Syrian hamster has provided the opportunity to create models for many of the human diseases for which there are either no existent animal models or severe limitations in the available animal models,” Dr Wang said.
Using an animal model they developed, researchers have identified a pathway that inhibits replication of the adenovirus.
The team generated a new strain of Syrian hamster, a model in which human adenovirus replicates and causes illness similar to that observed in humans.
Experiments with this model suggested the Type I interferon pathway plays a key role in inhibiting adenovirus replication.
“[L]ike many other viruses, adenovirus can replicate at will when a patient’s immune system is suppressed,” said William Wold, PhD, of Saint Louis University in Missouri.
“Adenovirus can become very dangerous, such as for a child who is undergoing a bone marrow transplant to treat leukemia.”
Previously, Dr Wold led a research team that identified the Syrian hamster as an appropriate animal model to study adenovirus because species C human adenoviruses replicate in these animals.
For the current study, which was published in PLOS Pathogens, Dr Wold and his colleagues conducted experiments with a new Syrian hamster strain. In these animals, the STAT2 gene was functionally knocked out by site-specific gene targeting.
The researchers found that STAT2-knockout hamsters were extremely sensitive to infection with type 5 human adenovirus (Ad5).
The team infected both STAT2-knockout hamsters and wild-type controls with Ad5. Knockout hamsters had 100 to 1000 times the viral load of controls.
The knockout hamsters also had pathology characteristic of advanced adenovirus infection—yellow, mottled livers and enlarged gall bladders—whereas controls did not.
The adaptive immune response to Ad5 remained intact in the STAT2-knockout hamsters, as surviving animals were able to clear the virus.
However, the Type 1 interferon response was hampered in these animals. Knocking out STAT2 disrupted the Type 1 interferon pathway by interrupting the cascade of cell signaling.
The researchers said their findings suggest the disrupted Type I interferon pathway contributed to the increased Ad5 replication in the STAT2-knockout hamsters.
“Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model,” Dr Wold said. “The STAT2-knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola, hanta, and dengue viruses.”
The model was created by Zhongde Wang, PhD, and his colleagues at Utah State University in Logan, Utah. Dr Wang’s lab is the first to develop gene-targeting technologies in the Syrian hamster.
“The success we achieved in conducting gene-targeting in the Syrian hamster has provided the opportunity to create models for many of the human diseases for which there are either no existent animal models or severe limitations in the available animal models,” Dr Wang said.
T-cell finding may have broad implications
resolution microscope
Image courtesy of UNSW
Early exposure to inflammatory cytokines can “paralyze” CD4 T cells, according to research published in Immunity.
The study suggests this mechanism may act as a firewall, shutting down the immune response before it gets out of hand.
According to researchers, this discovery could lead to more effective immunotherapies for cancer and reduce the need for immunosuppressants in transplant patients, among other applications.
“There’s a 3-signal process to activate T cells, of which each component is essential for proper activation,” said study author Gail Sckisel, PhD, of the University of California, Davis in Sacramento.
“But no one had really looked at what happens if they are delivered out of sequence. If the third signal—cytokines—is given prematurely, it basically paralyzes CD4 T cells.”
To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early—as is done with some immunotherapies—could actually hamper overall immunity.
“These stimulatory immunotherapies are designed to activate the immune system,” Dr Sckisel explained. “But considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.”
She and her colleagues demonstrated this principle in mice. After they received systemic immunotherapy, the animals had trouble mounting a primary T-cell response.
The researchers confirmed this finding in samples from patients receiving high-dose interleukin 2 to treat metastatic melanoma.
“We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss,” said study author William Murphy, PhD, also of the University of California, Davis.
“The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system.”
In addition to illuminating how T cells respond to cancer immunotherapy, the study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.
By shutting down CD4 T cells, immune stimulation prevented an autoimmune response. This provides the opportunity to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs.
“Transplant patients go on immunosuppressants for the rest of their lives, but if we could safely induce paralysis just prior to surgery, it’s possible that patients could develop tolerance,” Dr Sckisel said.
CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.
“This really highlights the importance of CD4 T cells,” Dr Murphy said. “The fact that they’re regulated and suppressed means they are definitely the orchestrators we need to take into account. It also shows how smart HIV is. The virus has been telling us CD4 T cells are critical because that’s what it attacks.”
The team’s next step is to continue this research in older mice. Age can bring a measurable loss in immune function, and inflammation may play a role in that process.
“For elderly people who have flu or pneumonia, their immune systems are activated, but maybe they can’t fight anything else,” Dr Murphy said. “This could change how we treat people who are very sick. If we can block pathways that suppress the immune response, we may be able to better fight infection.”
resolution microscope
Image courtesy of UNSW
Early exposure to inflammatory cytokines can “paralyze” CD4 T cells, according to research published in Immunity.
The study suggests this mechanism may act as a firewall, shutting down the immune response before it gets out of hand.
According to researchers, this discovery could lead to more effective immunotherapies for cancer and reduce the need for immunosuppressants in transplant patients, among other applications.
“There’s a 3-signal process to activate T cells, of which each component is essential for proper activation,” said study author Gail Sckisel, PhD, of the University of California, Davis in Sacramento.
“But no one had really looked at what happens if they are delivered out of sequence. If the third signal—cytokines—is given prematurely, it basically paralyzes CD4 T cells.”
To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early—as is done with some immunotherapies—could actually hamper overall immunity.
“These stimulatory immunotherapies are designed to activate the immune system,” Dr Sckisel explained. “But considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.”
She and her colleagues demonstrated this principle in mice. After they received systemic immunotherapy, the animals had trouble mounting a primary T-cell response.
The researchers confirmed this finding in samples from patients receiving high-dose interleukin 2 to treat metastatic melanoma.
“We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss,” said study author William Murphy, PhD, also of the University of California, Davis.
“The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system.”
In addition to illuminating how T cells respond to cancer immunotherapy, the study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.
By shutting down CD4 T cells, immune stimulation prevented an autoimmune response. This provides the opportunity to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs.
“Transplant patients go on immunosuppressants for the rest of their lives, but if we could safely induce paralysis just prior to surgery, it’s possible that patients could develop tolerance,” Dr Sckisel said.
CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.
“This really highlights the importance of CD4 T cells,” Dr Murphy said. “The fact that they’re regulated and suppressed means they are definitely the orchestrators we need to take into account. It also shows how smart HIV is. The virus has been telling us CD4 T cells are critical because that’s what it attacks.”
The team’s next step is to continue this research in older mice. Age can bring a measurable loss in immune function, and inflammation may play a role in that process.
“For elderly people who have flu or pneumonia, their immune systems are activated, but maybe they can’t fight anything else,” Dr Murphy said. “This could change how we treat people who are very sick. If we can block pathways that suppress the immune response, we may be able to better fight infection.”
resolution microscope
Image courtesy of UNSW
Early exposure to inflammatory cytokines can “paralyze” CD4 T cells, according to research published in Immunity.
The study suggests this mechanism may act as a firewall, shutting down the immune response before it gets out of hand.
According to researchers, this discovery could lead to more effective immunotherapies for cancer and reduce the need for immunosuppressants in transplant patients, among other applications.
“There’s a 3-signal process to activate T cells, of which each component is essential for proper activation,” said study author Gail Sckisel, PhD, of the University of California, Davis in Sacramento.
“But no one had really looked at what happens if they are delivered out of sequence. If the third signal—cytokines—is given prematurely, it basically paralyzes CD4 T cells.”
To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early—as is done with some immunotherapies—could actually hamper overall immunity.
“These stimulatory immunotherapies are designed to activate the immune system,” Dr Sckisel explained. “But considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.”
She and her colleagues demonstrated this principle in mice. After they received systemic immunotherapy, the animals had trouble mounting a primary T-cell response.
The researchers confirmed this finding in samples from patients receiving high-dose interleukin 2 to treat metastatic melanoma.
“We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss,” said study author William Murphy, PhD, also of the University of California, Davis.
“The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system.”
In addition to illuminating how T cells respond to cancer immunotherapy, the study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.
By shutting down CD4 T cells, immune stimulation prevented an autoimmune response. This provides the opportunity to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs.
“Transplant patients go on immunosuppressants for the rest of their lives, but if we could safely induce paralysis just prior to surgery, it’s possible that patients could develop tolerance,” Dr Sckisel said.
CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.
“This really highlights the importance of CD4 T cells,” Dr Murphy said. “The fact that they’re regulated and suppressed means they are definitely the orchestrators we need to take into account. It also shows how smart HIV is. The virus has been telling us CD4 T cells are critical because that’s what it attacks.”
The team’s next step is to continue this research in older mice. Age can bring a measurable loss in immune function, and inflammation may play a role in that process.
“For elderly people who have flu or pneumonia, their immune systems are activated, but maybe they can’t fight anything else,” Dr Murphy said. “This could change how we treat people who are very sick. If we can block pathways that suppress the immune response, we may be able to better fight infection.”
Team may have found earliest case of leukemia
archaeological dig
(male, Late Bronze Age)
Photo by Wessex Archaeology
ZURICH—Researchers may have discovered the earliest known case of leukemia by imaging a 7000-year-old skeleton.
High-resolution CT scans revealed locally defined trabecular bone resorption in the sternum and humerus, which strongly suggests a case of leukemia, according to the researchers.
Heike Scherf, PhD, of Eberhard Karls Universität Tübingen in Tübingen, Germany, and her colleagues presented this discovery at the Evolutionary Medicine Conference: Interdisciplinary Perspectives on Human Health and Disease (abstract P-07).
A poster describing the research is available on ResearchGate.
Dr Scherf and her colleagues described a skeleton recovered from the early Neolithic Linear Pottery Culture site Stuttgart-Muhlhausen in southwest Germany, which dates back to 5700-4900 BP.
The skeleton belonged to a woman who was thought to be 30 to 40 years old at the time of her death. Previous analysis had revealed a severe case of dental caries with alveolar inflammation in this woman.
The high-resolution CT scans revealed loss of trabecular bone in both the humerus and the sternum.
Dr Scherf and her colleagues said the level of trabecular resorption in this skeleton is significantly higher than that observed in specimens of the same age group from the same site, as well as in recent human samples.
The researchers were able to rule out other conditions that might explain the bone resorption, including osteoporosis, hyperparathyroidism, and solid tumor malignancy.
They said the locally restricted resorption at sites of hematopoietic stem cell generation strongly suggests leukemia in its initial stages, although they were unable to identify the subtype.
Still, if the researchers’ interpretation of their findings is correct, this is the earliest case of leukemia reported.
archaeological dig
(male, Late Bronze Age)
Photo by Wessex Archaeology
ZURICH—Researchers may have discovered the earliest known case of leukemia by imaging a 7000-year-old skeleton.
High-resolution CT scans revealed locally defined trabecular bone resorption in the sternum and humerus, which strongly suggests a case of leukemia, according to the researchers.
Heike Scherf, PhD, of Eberhard Karls Universität Tübingen in Tübingen, Germany, and her colleagues presented this discovery at the Evolutionary Medicine Conference: Interdisciplinary Perspectives on Human Health and Disease (abstract P-07).
A poster describing the research is available on ResearchGate.
Dr Scherf and her colleagues described a skeleton recovered from the early Neolithic Linear Pottery Culture site Stuttgart-Muhlhausen in southwest Germany, which dates back to 5700-4900 BP.
The skeleton belonged to a woman who was thought to be 30 to 40 years old at the time of her death. Previous analysis had revealed a severe case of dental caries with alveolar inflammation in this woman.
The high-resolution CT scans revealed loss of trabecular bone in both the humerus and the sternum.
Dr Scherf and her colleagues said the level of trabecular resorption in this skeleton is significantly higher than that observed in specimens of the same age group from the same site, as well as in recent human samples.
The researchers were able to rule out other conditions that might explain the bone resorption, including osteoporosis, hyperparathyroidism, and solid tumor malignancy.
They said the locally restricted resorption at sites of hematopoietic stem cell generation strongly suggests leukemia in its initial stages, although they were unable to identify the subtype.
Still, if the researchers’ interpretation of their findings is correct, this is the earliest case of leukemia reported.
archaeological dig
(male, Late Bronze Age)
Photo by Wessex Archaeology
ZURICH—Researchers may have discovered the earliest known case of leukemia by imaging a 7000-year-old skeleton.
High-resolution CT scans revealed locally defined trabecular bone resorption in the sternum and humerus, which strongly suggests a case of leukemia, according to the researchers.
Heike Scherf, PhD, of Eberhard Karls Universität Tübingen in Tübingen, Germany, and her colleagues presented this discovery at the Evolutionary Medicine Conference: Interdisciplinary Perspectives on Human Health and Disease (abstract P-07).
A poster describing the research is available on ResearchGate.
Dr Scherf and her colleagues described a skeleton recovered from the early Neolithic Linear Pottery Culture site Stuttgart-Muhlhausen in southwest Germany, which dates back to 5700-4900 BP.
The skeleton belonged to a woman who was thought to be 30 to 40 years old at the time of her death. Previous analysis had revealed a severe case of dental caries with alveolar inflammation in this woman.
The high-resolution CT scans revealed loss of trabecular bone in both the humerus and the sternum.
Dr Scherf and her colleagues said the level of trabecular resorption in this skeleton is significantly higher than that observed in specimens of the same age group from the same site, as well as in recent human samples.
The researchers were able to rule out other conditions that might explain the bone resorption, including osteoporosis, hyperparathyroidism, and solid tumor malignancy.
They said the locally restricted resorption at sites of hematopoietic stem cell generation strongly suggests leukemia in its initial stages, although they were unable to identify the subtype.
Still, if the researchers’ interpretation of their findings is correct, this is the earliest case of leukemia reported.
New HMA shows early promise for MDS/AML
Image by Christoph Bock
Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.
The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.
The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.
They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.
“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.
Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.
The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m2 to 125 mg/m2.
The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).
The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.
Safety and efficacy
The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).
The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).
There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m2 daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m2 daily × 5. The maximum tolerated dose was not reached in patients with AML.
Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m2. So the team recommended this as the phase 2 dose.
A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.
Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.
Image by Christoph Bock
Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.
The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.
The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.
They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.
“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.
Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.
The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m2 to 125 mg/m2.
The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).
The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.
Safety and efficacy
The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).
The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).
There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m2 daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m2 daily × 5. The maximum tolerated dose was not reached in patients with AML.
Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m2. So the team recommended this as the phase 2 dose.
A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.
Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.
Image by Christoph Bock
Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.
The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.
The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.
They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.
“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.
Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.
The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m2 to 125 mg/m2.
The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).
The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.
Safety and efficacy
The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).
The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).
There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m2 daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m2 daily × 5. The maximum tolerated dose was not reached in patients with AML.
Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m2. So the team recommended this as the phase 2 dose.
A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.
Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.
FDA approves new formulation of pain patch for cancer patients
receiving treatment
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved a new formulation of fentanyl buccal soluble film CII (Onsolis), a patch used to manage breakthrough pain in adult cancer patients who are opioid-tolerant.
This decision allows BioDelivery Sciences International, Inc. (BDSI), the company developing Onsolis, to bring the product back to the US marketplace.
However, the company said this will not happen before 2016.
Onsolis is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain.
Onsolis utilizes BioErodible MucoAdhesive drug delivery technology, which consists of a small, bioerodible polymer film that is applied to the inner lining of the cheek. Onsolis is the only differentiated fentanyl-containing product for this indication that provides buccal administration.
Onsolis off the US market
Onsolis was originally approved by the FDA in July 2009, but BDSI stopped manufacturing the product in March 2012, after the FDA uncovered 2 issues with Onsolis.
The FDA found that, during Onsolis’s 24-month shelf-life, microscopic crystals formed on the product, and the color faded slightly. BDSI said these changes did not affect the product’s underlying integrity or safety, but the FDA thought the fading color in particular might cause patients to question the product’s efficacy.
So the FDA required that Onsolis be modified before additional product could be manufactured and distributed. Supplies of Onsolis that were already on the market remained on the market.
An analysis by BDSI showed that the changes in Onsolis were related to an excipient used in the manufacturing process that could be removed to resolve the problem.
The excipient was specific to the manufacture of Onsolis in the US. Therefore, it did not impact the launch of Breakyl, which is the brand name for Onsolis in the European Union.
Return to market
After BDSI reformulated Onsolis to prevent the aforementioned changes in the product’s appearance, the FDA approved the product’s return to market.
“We are pleased to have obtained FDA approval of our [supplemental new drug application] and to now be in a position to move toward returning Onsolis to the US marketplace,” said Mark A. Sirgo, PharmD, President and Chief Executive Officer of BDSI.
“Although we have options for Onsolis, including commercializing it on our own, our current plan is to determine the value we can secure in a partnership with a company that has access to the target physician audience. We have been engaged with a number of potential partners, and, with this approval, we can now proceed forward with those discussions in earnest. We will provide more definitive timing in the near future about the reintroduction, but this would not be prior to 2016.”
Once Onsolis does return to the market, it will only be available via the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program. This is an FDA-required program designed to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines.
Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to receive Onsolis. Further information is available at www.TIRFREMSAccess.com.
receiving treatment
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved a new formulation of fentanyl buccal soluble film CII (Onsolis), a patch used to manage breakthrough pain in adult cancer patients who are opioid-tolerant.
This decision allows BioDelivery Sciences International, Inc. (BDSI), the company developing Onsolis, to bring the product back to the US marketplace.
However, the company said this will not happen before 2016.
Onsolis is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain.
Onsolis utilizes BioErodible MucoAdhesive drug delivery technology, which consists of a small, bioerodible polymer film that is applied to the inner lining of the cheek. Onsolis is the only differentiated fentanyl-containing product for this indication that provides buccal administration.
Onsolis off the US market
Onsolis was originally approved by the FDA in July 2009, but BDSI stopped manufacturing the product in March 2012, after the FDA uncovered 2 issues with Onsolis.
The FDA found that, during Onsolis’s 24-month shelf-life, microscopic crystals formed on the product, and the color faded slightly. BDSI said these changes did not affect the product’s underlying integrity or safety, but the FDA thought the fading color in particular might cause patients to question the product’s efficacy.
So the FDA required that Onsolis be modified before additional product could be manufactured and distributed. Supplies of Onsolis that were already on the market remained on the market.
An analysis by BDSI showed that the changes in Onsolis were related to an excipient used in the manufacturing process that could be removed to resolve the problem.
The excipient was specific to the manufacture of Onsolis in the US. Therefore, it did not impact the launch of Breakyl, which is the brand name for Onsolis in the European Union.
Return to market
After BDSI reformulated Onsolis to prevent the aforementioned changes in the product’s appearance, the FDA approved the product’s return to market.
“We are pleased to have obtained FDA approval of our [supplemental new drug application] and to now be in a position to move toward returning Onsolis to the US marketplace,” said Mark A. Sirgo, PharmD, President and Chief Executive Officer of BDSI.
“Although we have options for Onsolis, including commercializing it on our own, our current plan is to determine the value we can secure in a partnership with a company that has access to the target physician audience. We have been engaged with a number of potential partners, and, with this approval, we can now proceed forward with those discussions in earnest. We will provide more definitive timing in the near future about the reintroduction, but this would not be prior to 2016.”
Once Onsolis does return to the market, it will only be available via the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program. This is an FDA-required program designed to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines.
Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to receive Onsolis. Further information is available at www.TIRFREMSAccess.com.
receiving treatment
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved a new formulation of fentanyl buccal soluble film CII (Onsolis), a patch used to manage breakthrough pain in adult cancer patients who are opioid-tolerant.
This decision allows BioDelivery Sciences International, Inc. (BDSI), the company developing Onsolis, to bring the product back to the US marketplace.
However, the company said this will not happen before 2016.
Onsolis is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain.
Onsolis utilizes BioErodible MucoAdhesive drug delivery technology, which consists of a small, bioerodible polymer film that is applied to the inner lining of the cheek. Onsolis is the only differentiated fentanyl-containing product for this indication that provides buccal administration.
Onsolis off the US market
Onsolis was originally approved by the FDA in July 2009, but BDSI stopped manufacturing the product in March 2012, after the FDA uncovered 2 issues with Onsolis.
The FDA found that, during Onsolis’s 24-month shelf-life, microscopic crystals formed on the product, and the color faded slightly. BDSI said these changes did not affect the product’s underlying integrity or safety, but the FDA thought the fading color in particular might cause patients to question the product’s efficacy.
So the FDA required that Onsolis be modified before additional product could be manufactured and distributed. Supplies of Onsolis that were already on the market remained on the market.
An analysis by BDSI showed that the changes in Onsolis were related to an excipient used in the manufacturing process that could be removed to resolve the problem.
The excipient was specific to the manufacture of Onsolis in the US. Therefore, it did not impact the launch of Breakyl, which is the brand name for Onsolis in the European Union.
Return to market
After BDSI reformulated Onsolis to prevent the aforementioned changes in the product’s appearance, the FDA approved the product’s return to market.
“We are pleased to have obtained FDA approval of our [supplemental new drug application] and to now be in a position to move toward returning Onsolis to the US marketplace,” said Mark A. Sirgo, PharmD, President and Chief Executive Officer of BDSI.
“Although we have options for Onsolis, including commercializing it on our own, our current plan is to determine the value we can secure in a partnership with a company that has access to the target physician audience. We have been engaged with a number of potential partners, and, with this approval, we can now proceed forward with those discussions in earnest. We will provide more definitive timing in the near future about the reintroduction, but this would not be prior to 2016.”
Once Onsolis does return to the market, it will only be available via the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program. This is an FDA-required program designed to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines.
Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to receive Onsolis. Further information is available at www.TIRFREMSAccess.com.
The LAST Study: CML trial examines life after TKIs
In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.
Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.
All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.
Click here to learn more about The LAST Study.
In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.
Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.
All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.
Click here to learn more about The LAST Study.
In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.
Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.
All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.
Click here to learn more about The LAST Study.
FROM CLINICALTRIALS.GOV
Algorithm can enhance clustering, aid trial design
Chenyue Wendy Hu
Photo courtesy of Jeff Fitlow
and Rice University
A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.
The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.
And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.
Details on progeny clustering have been published in Scientific Reports.
The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.
“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”
The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.
“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”
Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.
These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.
By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.
Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.
And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.
Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.
The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.
“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”
Dr Qutub added that the algorithm could apply to any data set.
“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”
Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.
Chenyue Wendy Hu
Photo courtesy of Jeff Fitlow
and Rice University
A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.
The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.
And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.
Details on progeny clustering have been published in Scientific Reports.
The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.
“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”
The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.
“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”
Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.
These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.
By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.
Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.
And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.
Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.
The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.
“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”
Dr Qutub added that the algorithm could apply to any data set.
“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”
Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.
Chenyue Wendy Hu
Photo courtesy of Jeff Fitlow
and Rice University
A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.
The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.
And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.
Details on progeny clustering have been published in Scientific Reports.
The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.
“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”
The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.
“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”
Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.
These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.
By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.
Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.
And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.
Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.
The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.
“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”
Dr Qutub added that the algorithm could apply to any data set.
“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”
Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.
Tool that lets patients report AEs proves reliable
receiving chemotherapy
Photo by Rhoda Baer
Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.
The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.
The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.
This research was published in JAMA Oncology.
“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.
“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”
To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.
The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.
The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).
Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.
To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.
Construct validity
The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.
Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.
When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).
Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).
Test-retest reliability and responsiveness
The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.
Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).
The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.
Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).
“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.
receiving chemotherapy
Photo by Rhoda Baer
Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.
The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.
The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.
This research was published in JAMA Oncology.
“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.
“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”
To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.
The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.
The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).
Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.
To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.
Construct validity
The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.
Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.
When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).
Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).
Test-retest reliability and responsiveness
The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.
Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).
The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.
Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).
“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.
receiving chemotherapy
Photo by Rhoda Baer
Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.
The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.
The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.
This research was published in JAMA Oncology.
“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.
“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”
To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.
The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.
The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).
Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.
To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.
Construct validity
The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.
Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.
When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).
Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).
Test-retest reliability and responsiveness
The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.
Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).
The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.
Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).
“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.
How CLL evades the immune system
Photo courtesy of
Monash University
A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.
“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.
She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.
The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.
The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.
“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”
“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”
Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.
“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”
Photo courtesy of
Monash University
A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.
“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.
She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.
The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.
The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.
“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”
“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”
Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.
“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”
Photo courtesy of
Monash University
A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.
“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.
She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.
The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.
The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.
“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”
“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”
Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.
“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”
Groups draft guidelines for acute leukemia
Photo courtesy of the CDC
The American Society of Hematology (ASH) and the College of American Pathologists (CAP) have opened a public comment period for a draft guideline that addresses the initial work-up of acute leukemia.
The guideline details the information required for the diagnosis of acute leukemias, as well as recommended testing and how test results and diagnosis should be correlated.
The document will be available for comment through August 31.
The guideline authors examined evidence from more than 170 articles to devise the draft guidelines. The resulting document answers the following questions:
- What clinical and laboratory information should be available during the initial diagnostic evaluation of a patient with acute leukemia?
- What specimens and sample types should be evaluated during the initial work-up of a patient with acute leukemia?
- At the time of diagnosis, what tests are required for all patients for the initial evaluation of an acute leukemia?
- What tests should be performed only on a subset of patients, including in response to results of initial tests and morphology?
- Where should testing be performed?
- How should test results and the diagnosis be correlated and reported?
“Evidence-based guidelines like these are increasingly vital to the continued improvement and continuity of patient care,” said ASH guideline co-chair James W. Vardiman, MD, of the University of Chicago in Illinois.
He and Daniel A. Arber, MD, of Stanford School of Medicine in California, (the CAP representative co-chair) are leading an interdisciplinary team of 8 physicians representing sub-specialties that include hematopathology and oncology.
“Our work on these guidelines aims at integrating the very best practices to improve outcomes for [acute leukemia] patients and their families,” Dr Arber said.
At the close of the comment period, the CAP/ASH team will review any comments and make final recommendations, which are targeted for publication in the first quarter of 2016.
Photo courtesy of the CDC
The American Society of Hematology (ASH) and the College of American Pathologists (CAP) have opened a public comment period for a draft guideline that addresses the initial work-up of acute leukemia.
The guideline details the information required for the diagnosis of acute leukemias, as well as recommended testing and how test results and diagnosis should be correlated.
The document will be available for comment through August 31.
The guideline authors examined evidence from more than 170 articles to devise the draft guidelines. The resulting document answers the following questions:
- What clinical and laboratory information should be available during the initial diagnostic evaluation of a patient with acute leukemia?
- What specimens and sample types should be evaluated during the initial work-up of a patient with acute leukemia?
- At the time of diagnosis, what tests are required for all patients for the initial evaluation of an acute leukemia?
- What tests should be performed only on a subset of patients, including in response to results of initial tests and morphology?
- Where should testing be performed?
- How should test results and the diagnosis be correlated and reported?
“Evidence-based guidelines like these are increasingly vital to the continued improvement and continuity of patient care,” said ASH guideline co-chair James W. Vardiman, MD, of the University of Chicago in Illinois.
He and Daniel A. Arber, MD, of Stanford School of Medicine in California, (the CAP representative co-chair) are leading an interdisciplinary team of 8 physicians representing sub-specialties that include hematopathology and oncology.
“Our work on these guidelines aims at integrating the very best practices to improve outcomes for [acute leukemia] patients and their families,” Dr Arber said.
At the close of the comment period, the CAP/ASH team will review any comments and make final recommendations, which are targeted for publication in the first quarter of 2016.
Photo courtesy of the CDC
The American Society of Hematology (ASH) and the College of American Pathologists (CAP) have opened a public comment period for a draft guideline that addresses the initial work-up of acute leukemia.
The guideline details the information required for the diagnosis of acute leukemias, as well as recommended testing and how test results and diagnosis should be correlated.
The document will be available for comment through August 31.
The guideline authors examined evidence from more than 170 articles to devise the draft guidelines. The resulting document answers the following questions:
- What clinical and laboratory information should be available during the initial diagnostic evaluation of a patient with acute leukemia?
- What specimens and sample types should be evaluated during the initial work-up of a patient with acute leukemia?
- At the time of diagnosis, what tests are required for all patients for the initial evaluation of an acute leukemia?
- What tests should be performed only on a subset of patients, including in response to results of initial tests and morphology?
- Where should testing be performed?
- How should test results and the diagnosis be correlated and reported?
“Evidence-based guidelines like these are increasingly vital to the continued improvement and continuity of patient care,” said ASH guideline co-chair James W. Vardiman, MD, of the University of Chicago in Illinois.
He and Daniel A. Arber, MD, of Stanford School of Medicine in California, (the CAP representative co-chair) are leading an interdisciplinary team of 8 physicians representing sub-specialties that include hematopathology and oncology.
“Our work on these guidelines aims at integrating the very best practices to improve outcomes for [acute leukemia] patients and their families,” Dr Arber said.
At the close of the comment period, the CAP/ASH team will review any comments and make final recommendations, which are targeted for publication in the first quarter of 2016.