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Survival differences among AYAs with blood cancers
A new report has revealed differences in survival among adolescents and young adults (AYAs) with hematologic malignancies.
The report includes information on AYAs—ages 15 to 39—living in Los Angeles County who were diagnosed with common cancers between 1988 and 2014.
The data showed differences in 5-year survival rates according to sex, race, age, and socioeconomic status (SES).
For example, lymphoma survival rates were lower for males, African Americans (AAs), older AYAs, and patients with low socioeconomic status (SES).
For AYAs with leukemias, there was no survival difference according to sex, but AAs had worse survival than patients of other races. And the impact of age and SES varied according to leukemia type.
“Cancer survival data are poorly understood for 15- to 39-year-olds,” noted Amie Hwang, PhD, of the University of Southern California Keck School of Medicine in Los Angeles.
That is why she and her colleagues created the report, “Cancer in Los Angeles County: Survival Among Adolescents and Young Adults 1988-2014.”
According to the authors, this is the first report to break down cancer survival rates for AYAs into segments on race/ethnicity, sex, age group, SES, and cancer stage.
Survival data for patients with hematologic malignancies were as follows.
Acute lymphoblastic leukemia
There were 1137 cases of acute lymphoblastic leukemia in the AYA population in Los Angeles County during the period studied. This included 752 males and 385 females.
Five-year survival was similar between males (43%) and females (41%).
Younger AYAs had better survival than older AYAs (48% for ages 15-24, 35% for ages 25-34, and 32% for ages 35-39).
Survival was highest among non-Latino whites (NLWs, 56%), followed by Asian/Pacific Islanders (APIs, 52%), patients of other/unknown races (51%), Latino whites (LWs, 38%), and AAs (29%).
Survival declined with SES (55% for high, 42% for middle, and 36% for low SES).
Acute myeloid leukemia
There were 1195 cases of acute myeloid leukemia—641 males and 554 females.
Five-year survival was similar for males (40%) and females (43%) as well as for the different age groups (45% for ages 15-24 vs 40% for the older age groups).
Survival was highest among NLWs (44%), followed by LWs (43%), APIs (40%), other/unknown (33%), and AAs (25%).
Survival declined somewhat with SES (49% for high, 39% for middle, and 41% for low SES).
Chronic myeloid leukemia
There were 655 cases of chronic myeloid leukemia—408 males and 247 females.
Five-year survival was similar for males (70%) and females (71%), but it was slightly higher for older AYAs (69% for ages 15-24, 68% for ages 25-34, and 76% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (76%), followed by LWs (73%), NLWs/APIs (both 72%), and AAs (57%).
Survival declined somewhat with SES (76% for high, 67% for middle, and 68% for low SES).
Hodgkin lymphoma
There were 2993 AYAs diagnosed with Hodgkin lymphoma—1553 males and 1440 females.
The 5-year survival rate was higher in females (93%) than males (86%) and in younger AYAs (93% for ages 15-24, 89% for ages 25-34, and 85% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (96%), followed by APIs/NLWs (both 91%), LWs (88%), and AAs (83%).
Survival declined with SES (95% for high, 89% for middle, and 83% for low SES).
And survival was lower for patients with advanced-stage disease (93% localized, 94% regional, and 83% distant).
Non-Hodkgin lymphoma
There were 4485 AYAs diagnosed with non-Hodgkin lymphoma during the study period—3064 males and 1421 females.
The 5-year survival rate was higher in females (75%) than males (46%) and in younger AYAs (69% for ages 15-24, 51% for ages 25-34, and 52% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (88%), followed by APIs (68%), LWs/NLWs (both 53%), and AAs (50%).
Survival declined with SES (68% for high, 54% for middle, and 45% for low SES).
And survival was lower for patients with advanced-stage disease (61% localized, 66% regional, and 46% distant).
“Adolescents and young adults go to the doctor less often because they have this superhero mentality, like they’re invincible,” said author Dennis Deapen, DrPH, of the University of Southern California Keck School of Medicine.
“Once they do go to a health professional, their cancer diagnosis can be delayed because cancer isn’t the first concern doctors have for this age group. It comes as no surprise that patients diagnosed with late-stage cancer have reduced survival rates.” 
A new report has revealed differences in survival among adolescents and young adults (AYAs) with hematologic malignancies.
The report includes information on AYAs—ages 15 to 39—living in Los Angeles County who were diagnosed with common cancers between 1988 and 2014.
The data showed differences in 5-year survival rates according to sex, race, age, and socioeconomic status (SES).
For example, lymphoma survival rates were lower for males, African Americans (AAs), older AYAs, and patients with low socioeconomic status (SES).
For AYAs with leukemias, there was no survival difference according to sex, but AAs had worse survival than patients of other races. And the impact of age and SES varied according to leukemia type.
“Cancer survival data are poorly understood for 15- to 39-year-olds,” noted Amie Hwang, PhD, of the University of Southern California Keck School of Medicine in Los Angeles.
That is why she and her colleagues created the report, “Cancer in Los Angeles County: Survival Among Adolescents and Young Adults 1988-2014.”
According to the authors, this is the first report to break down cancer survival rates for AYAs into segments on race/ethnicity, sex, age group, SES, and cancer stage.
Survival data for patients with hematologic malignancies were as follows.
Acute lymphoblastic leukemia
There were 1137 cases of acute lymphoblastic leukemia in the AYA population in Los Angeles County during the period studied. This included 752 males and 385 females.
Five-year survival was similar between males (43%) and females (41%).
Younger AYAs had better survival than older AYAs (48% for ages 15-24, 35% for ages 25-34, and 32% for ages 35-39).
Survival was highest among non-Latino whites (NLWs, 56%), followed by Asian/Pacific Islanders (APIs, 52%), patients of other/unknown races (51%), Latino whites (LWs, 38%), and AAs (29%).
Survival declined with SES (55% for high, 42% for middle, and 36% for low SES).
Acute myeloid leukemia
There were 1195 cases of acute myeloid leukemia—641 males and 554 females.
Five-year survival was similar for males (40%) and females (43%) as well as for the different age groups (45% for ages 15-24 vs 40% for the older age groups).
Survival was highest among NLWs (44%), followed by LWs (43%), APIs (40%), other/unknown (33%), and AAs (25%).
Survival declined somewhat with SES (49% for high, 39% for middle, and 41% for low SES).
Chronic myeloid leukemia
There were 655 cases of chronic myeloid leukemia—408 males and 247 females.
Five-year survival was similar for males (70%) and females (71%), but it was slightly higher for older AYAs (69% for ages 15-24, 68% for ages 25-34, and 76% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (76%), followed by LWs (73%), NLWs/APIs (both 72%), and AAs (57%).
Survival declined somewhat with SES (76% for high, 67% for middle, and 68% for low SES).
Hodgkin lymphoma
There were 2993 AYAs diagnosed with Hodgkin lymphoma—1553 males and 1440 females.
The 5-year survival rate was higher in females (93%) than males (86%) and in younger AYAs (93% for ages 15-24, 89% for ages 25-34, and 85% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (96%), followed by APIs/NLWs (both 91%), LWs (88%), and AAs (83%).
Survival declined with SES (95% for high, 89% for middle, and 83% for low SES).
And survival was lower for patients with advanced-stage disease (93% localized, 94% regional, and 83% distant).
Non-Hodkgin lymphoma
There were 4485 AYAs diagnosed with non-Hodgkin lymphoma during the study period—3064 males and 1421 females.
The 5-year survival rate was higher in females (75%) than males (46%) and in younger AYAs (69% for ages 15-24, 51% for ages 25-34, and 52% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (88%), followed by APIs (68%), LWs/NLWs (both 53%), and AAs (50%).
Survival declined with SES (68% for high, 54% for middle, and 45% for low SES).
And survival was lower for patients with advanced-stage disease (61% localized, 66% regional, and 46% distant).
“Adolescents and young adults go to the doctor less often because they have this superhero mentality, like they’re invincible,” said author Dennis Deapen, DrPH, of the University of Southern California Keck School of Medicine.
“Once they do go to a health professional, their cancer diagnosis can be delayed because cancer isn’t the first concern doctors have for this age group. It comes as no surprise that patients diagnosed with late-stage cancer have reduced survival rates.”
A new report has revealed differences in survival among adolescents and young adults (AYAs) with hematologic malignancies.
The report includes information on AYAs—ages 15 to 39—living in Los Angeles County who were diagnosed with common cancers between 1988 and 2014.
The data showed differences in 5-year survival rates according to sex, race, age, and socioeconomic status (SES).
For example, lymphoma survival rates were lower for males, African Americans (AAs), older AYAs, and patients with low socioeconomic status (SES).
For AYAs with leukemias, there was no survival difference according to sex, but AAs had worse survival than patients of other races. And the impact of age and SES varied according to leukemia type.
“Cancer survival data are poorly understood for 15- to 39-year-olds,” noted Amie Hwang, PhD, of the University of Southern California Keck School of Medicine in Los Angeles.
That is why she and her colleagues created the report, “Cancer in Los Angeles County: Survival Among Adolescents and Young Adults 1988-2014.”
According to the authors, this is the first report to break down cancer survival rates for AYAs into segments on race/ethnicity, sex, age group, SES, and cancer stage.
Survival data for patients with hematologic malignancies were as follows.
Acute lymphoblastic leukemia
There were 1137 cases of acute lymphoblastic leukemia in the AYA population in Los Angeles County during the period studied. This included 752 males and 385 females.
Five-year survival was similar between males (43%) and females (41%).
Younger AYAs had better survival than older AYAs (48% for ages 15-24, 35% for ages 25-34, and 32% for ages 35-39).
Survival was highest among non-Latino whites (NLWs, 56%), followed by Asian/Pacific Islanders (APIs, 52%), patients of other/unknown races (51%), Latino whites (LWs, 38%), and AAs (29%).
Survival declined with SES (55% for high, 42% for middle, and 36% for low SES).
Acute myeloid leukemia
There were 1195 cases of acute myeloid leukemia—641 males and 554 females.
Five-year survival was similar for males (40%) and females (43%) as well as for the different age groups (45% for ages 15-24 vs 40% for the older age groups).
Survival was highest among NLWs (44%), followed by LWs (43%), APIs (40%), other/unknown (33%), and AAs (25%).
Survival declined somewhat with SES (49% for high, 39% for middle, and 41% for low SES).
Chronic myeloid leukemia
There were 655 cases of chronic myeloid leukemia—408 males and 247 females.
Five-year survival was similar for males (70%) and females (71%), but it was slightly higher for older AYAs (69% for ages 15-24, 68% for ages 25-34, and 76% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (76%), followed by LWs (73%), NLWs/APIs (both 72%), and AAs (57%).
Survival declined somewhat with SES (76% for high, 67% for middle, and 68% for low SES).
Hodgkin lymphoma
There were 2993 AYAs diagnosed with Hodgkin lymphoma—1553 males and 1440 females.
The 5-year survival rate was higher in females (93%) than males (86%) and in younger AYAs (93% for ages 15-24, 89% for ages 25-34, and 85% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (96%), followed by APIs/NLWs (both 91%), LWs (88%), and AAs (83%).
Survival declined with SES (95% for high, 89% for middle, and 83% for low SES).
And survival was lower for patients with advanced-stage disease (93% localized, 94% regional, and 83% distant).
Non-Hodkgin lymphoma
There were 4485 AYAs diagnosed with non-Hodgkin lymphoma during the study period—3064 males and 1421 females.
The 5-year survival rate was higher in females (75%) than males (46%) and in younger AYAs (69% for ages 15-24, 51% for ages 25-34, and 52% for ages 35-39).
Survival was highest among patients in the “other/unknown” race category (88%), followed by APIs (68%), LWs/NLWs (both 53%), and AAs (50%).
Survival declined with SES (68% for high, 54% for middle, and 45% for low SES).
And survival was lower for patients with advanced-stage disease (61% localized, 66% regional, and 46% distant).
“Adolescents and young adults go to the doctor less often because they have this superhero mentality, like they’re invincible,” said author Dennis Deapen, DrPH, of the University of Southern California Keck School of Medicine.
“Once they do go to a health professional, their cancer diagnosis can be delayed because cancer isn’t the first concern doctors have for this age group. It comes as no surprise that patients diagnosed with late-stage cancer have reduced survival rates.”
Marine animals aid development of cytotoxicity assay
Researchers have looked to deep-sea creatures with the goal of creating a better cytotoxicity assay.
The team harnessed the power of enzymes responsible for marine animal bioluminescence to create the “Matador assay,” which can be used to determine whether cellular and immune-therapeutic agents are actually killing target cells.
The researchers said the Matador assay is quick and simple as well as “highly sensitive,” with the ability to detect cytotoxicity induced by several types of therapies.
Preet M. Chaudhary, MD, PhD, of the University of Southern California Keck School of Medicine in Los Angeles, and his colleagues described the assay in Scientific Reports.
“One of the most promising areas in cancer research is immunotherapy. . .,” Dr Chaudhary said. “It is also one of the most difficult because the methods for testing immunotherapies are not ideal.”
“Radioactive chromium release assay is the gold standard for testing whether an immunotherapy kills cancer cells. This method is expensive, complicated, and requires special disposal practices. Other available methods also suffer from limitations and don’t allow scientists to rapidly screen immunotherapeutic agents to find the best candidates.”
Dr Chaudhary and his colleagues set out to develop a simple, precise, and inexpensive cytotoxicity assay based on marine animal luciferases, the enzymes responsible for bioluminescence.
The team used a group of small crustaceans and deep-sea shrimp, which were selected for their bright bioluminescence. Their luciferases became the basis of the Matador assay.
Engineered to get trapped inside cells, the luciferases leak out of cells when they die, causing a visible glow. The level of luminescence can then be measured with a luminometer.
To test the Matador assay’s effectiveness at measuring cell death, the researchers used several types of cancer cells, including chronic myelogenous leukemia, acute myelogenous leukemia, Burkitt lymphoma, and solid tumor cells.
The team treated these cells with a variety of therapies, including chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers, monoclonal antibodies, and natural killer cells.
Results showed the Matador assay could detect the death of a single cell, a level of sensitivity superior to that of existing cytotoxicity assays.
The researchers also pointed out that the Matador assay is fast, inexpensive, and can be performed in a 384-well plate format, saving time and reagents.
“In our hands, the Matador assay can detect cell death in as little as 30 minutes, which can ultimately translate to more expedient treatments for patients getting cellular immunotherapies such as CAR T cells,” Dr Chaudhary said.
In fact, Dr Chaudhary’s lab has developed more than 75 cancer cell lines expressing the marine luciferases and used them with the Matador assay to develop next-generation CAR T cells.
Dr Chaudhary believes the Matador assay has many potential applications in biomedical research and cellular therapy manufacturing.
“It could potentially play a role in screening other types of anticancer agents or even measuring environmental toxins,” he said.
Researchers have looked to deep-sea creatures with the goal of creating a better cytotoxicity assay.
The team harnessed the power of enzymes responsible for marine animal bioluminescence to create the “Matador assay,” which can be used to determine whether cellular and immune-therapeutic agents are actually killing target cells.
The researchers said the Matador assay is quick and simple as well as “highly sensitive,” with the ability to detect cytotoxicity induced by several types of therapies.
Preet M. Chaudhary, MD, PhD, of the University of Southern California Keck School of Medicine in Los Angeles, and his colleagues described the assay in Scientific Reports.
“One of the most promising areas in cancer research is immunotherapy. . .,” Dr Chaudhary said. “It is also one of the most difficult because the methods for testing immunotherapies are not ideal.”
“Radioactive chromium release assay is the gold standard for testing whether an immunotherapy kills cancer cells. This method is expensive, complicated, and requires special disposal practices. Other available methods also suffer from limitations and don’t allow scientists to rapidly screen immunotherapeutic agents to find the best candidates.”
Dr Chaudhary and his colleagues set out to develop a simple, precise, and inexpensive cytotoxicity assay based on marine animal luciferases, the enzymes responsible for bioluminescence.
The team used a group of small crustaceans and deep-sea shrimp, which were selected for their bright bioluminescence. Their luciferases became the basis of the Matador assay.
Engineered to get trapped inside cells, the luciferases leak out of cells when they die, causing a visible glow. The level of luminescence can then be measured with a luminometer.
To test the Matador assay’s effectiveness at measuring cell death, the researchers used several types of cancer cells, including chronic myelogenous leukemia, acute myelogenous leukemia, Burkitt lymphoma, and solid tumor cells.
The team treated these cells with a variety of therapies, including chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers, monoclonal antibodies, and natural killer cells.
Results showed the Matador assay could detect the death of a single cell, a level of sensitivity superior to that of existing cytotoxicity assays.
The researchers also pointed out that the Matador assay is fast, inexpensive, and can be performed in a 384-well plate format, saving time and reagents.
“In our hands, the Matador assay can detect cell death in as little as 30 minutes, which can ultimately translate to more expedient treatments for patients getting cellular immunotherapies such as CAR T cells,” Dr Chaudhary said.
In fact, Dr Chaudhary’s lab has developed more than 75 cancer cell lines expressing the marine luciferases and used them with the Matador assay to develop next-generation CAR T cells.
Dr Chaudhary believes the Matador assay has many potential applications in biomedical research and cellular therapy manufacturing.
“It could potentially play a role in screening other types of anticancer agents or even measuring environmental toxins,” he said.
Researchers have looked to deep-sea creatures with the goal of creating a better cytotoxicity assay.
The team harnessed the power of enzymes responsible for marine animal bioluminescence to create the “Matador assay,” which can be used to determine whether cellular and immune-therapeutic agents are actually killing target cells.
The researchers said the Matador assay is quick and simple as well as “highly sensitive,” with the ability to detect cytotoxicity induced by several types of therapies.
Preet M. Chaudhary, MD, PhD, of the University of Southern California Keck School of Medicine in Los Angeles, and his colleagues described the assay in Scientific Reports.
“One of the most promising areas in cancer research is immunotherapy. . .,” Dr Chaudhary said. “It is also one of the most difficult because the methods for testing immunotherapies are not ideal.”
“Radioactive chromium release assay is the gold standard for testing whether an immunotherapy kills cancer cells. This method is expensive, complicated, and requires special disposal practices. Other available methods also suffer from limitations and don’t allow scientists to rapidly screen immunotherapeutic agents to find the best candidates.”
Dr Chaudhary and his colleagues set out to develop a simple, precise, and inexpensive cytotoxicity assay based on marine animal luciferases, the enzymes responsible for bioluminescence.
The team used a group of small crustaceans and deep-sea shrimp, which were selected for their bright bioluminescence. Their luciferases became the basis of the Matador assay.
Engineered to get trapped inside cells, the luciferases leak out of cells when they die, causing a visible glow. The level of luminescence can then be measured with a luminometer.
To test the Matador assay’s effectiveness at measuring cell death, the researchers used several types of cancer cells, including chronic myelogenous leukemia, acute myelogenous leukemia, Burkitt lymphoma, and solid tumor cells.
The team treated these cells with a variety of therapies, including chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers, monoclonal antibodies, and natural killer cells.
Results showed the Matador assay could detect the death of a single cell, a level of sensitivity superior to that of existing cytotoxicity assays.
The researchers also pointed out that the Matador assay is fast, inexpensive, and can be performed in a 384-well plate format, saving time and reagents.
“In our hands, the Matador assay can detect cell death in as little as 30 minutes, which can ultimately translate to more expedient treatments for patients getting cellular immunotherapies such as CAR T cells,” Dr Chaudhary said.
In fact, Dr Chaudhary’s lab has developed more than 75 cancer cell lines expressing the marine luciferases and used them with the Matador assay to develop next-generation CAR T cells.
Dr Chaudhary believes the Matador assay has many potential applications in biomedical research and cellular therapy manufacturing.
“It could potentially play a role in screening other types of anticancer agents or even measuring environmental toxins,” he said.
Team finds way to target MYB in AML
Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”
Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”
Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”
DNA sequencing could help identify relapse risk in treated AML
ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.
Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.
They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.
More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.
To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.
The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.
They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.
About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).
Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.
However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).
Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).
When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).
NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).
In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).
When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.
The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.
Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.
They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.
More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.
To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.
The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.
They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.
About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).
Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.
However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).
Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).
When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).
NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).
In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).
When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.
The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.
Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.
They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.
More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.
To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.
The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.
They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.
About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).
Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.
However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).
Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).
When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).
NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).
In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).
When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.
The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The presence of any non-DTA mutation after CR was an independent prognostic factor for relapse (SHR 1.89) and overall survival (HR 1.64).
Study details: Prospective analysis of bone marrow samples from 430 patients with AML at diagnosis and in first complete remission.
Disclosures: The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
Source: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
CX-01 receives orphan designation for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.
HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).
The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).
Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.
The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.
With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.
No adverse events related to CX-01 were reported.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.
HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).
The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).
Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.
The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.
With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.
No adverse events related to CX-01 were reported.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CX-01 for the treatment of acute myeloid leukemia (AML).
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4.
HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy. The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were presented at the 2015 ASCO Annual Meeting (abstract 7053).
The study enrolled 12 adults with newly diagnosed AML. They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin, 7+3).
Eleven patients (92%), all of whom had de novo AML, had a complete response (CR) with a single induction cycle.
The median time to neutrophil recovery was 23 days, and the median time to platelet recovery was 22 days.
With a median follow-up of 14.2 months, the median event-free survival exceeded 11.6 months, and the median overall survival exceeded 13.6 months.
No adverse events related to CX-01 were reported.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Sorafenib plus chemo prolongs event-free survival in AML
ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.
At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.
Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.
In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.
Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) plus cytarabine (100 mg/m2 on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).
Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.
The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).
The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.
At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.
A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.
Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).
Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.
Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.
Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.
OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).
During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.
“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.
Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.
The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
SOURCE: Röllig C et al. ASH 2017 Abstract 721.
ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.
At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.
Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.
In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.
Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) plus cytarabine (100 mg/m2 on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).
Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.
The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).
The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.
At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.
A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.
Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).
Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.
Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.
Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.
OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).
During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.
“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.
Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.
The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
SOURCE: Röllig C et al. ASH 2017 Abstract 721.
ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.
At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.
Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.
In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.
Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) plus cytarabine (100 mg/m2 on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).
Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.
The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).
The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.
At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.
A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.
Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).
Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.
Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.
Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.
OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).
During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.
“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.
Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.
The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
SOURCE: Röllig C et al. ASH 2017 Abstract 721.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: At a median of 6.5 years, the hazard ratio for progression or death with sorafenib plus chemotherapy versus placebo plus chemotherapy was 0.68 (P = .011).
Data source: Randomized, double-blind, phase 2 trial comprising 267 patients with de novo AML.
Disclosures: The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and from Janssen; he also reported off-label use of sorafenib.
Source: Röllig C et al. ASH 2017 Abstract 721.
FDA lifts hold on trial of SEL24 in AML
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.
The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.
The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.
The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.
The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.
The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.
The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.
In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.
The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.
The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.
The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.
The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.
The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.
The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.
The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.
In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.
The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.
The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.
The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.
The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.
The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.
The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.
The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.
In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.
The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.
Iron chelating agent could enhance chemo in AML
Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.
Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.
However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.
“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”
For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.
The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.
This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.
Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.
The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.
The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.
The team compared Fbxw7iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.
After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.
Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.
However, after treatment, the Fbxw7iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.
The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.
“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.
Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.
Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.
Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.
However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.
“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”
For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.
The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.
This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.
Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.
The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.
The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.
The team compared Fbxw7iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.
After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.
Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.
However, after treatment, the Fbxw7iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.
The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.
“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.
Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.
Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.
Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.
However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.
“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”
For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.
The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.
This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.
Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.
The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.
The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.
The team compared Fbxw7iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.
After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.
Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.
However, after treatment, the Fbxw7iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.
The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.
“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.
Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.
FDA grants orphan designation to drug for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).
CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.
In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.
In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.
Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.
“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.
“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).
CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.
In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.
In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.
Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.
“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.
“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).
CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.
In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.
In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.
Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.
“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.
“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
VIDEO: Joint FDA-ASH session highlights new AML drugs
ATLANTA – The past year brought a flurry of new drug approvals for the treatment of acute myeloid leukemia (AML), including CPX-351, midostaurin, gemtuzumab ozogamicin, and enasidenib.
During a special interest session at the annual meeting of the American Society of Hematology, Food and Drug Administration representatives discussed the available data and approval process for these drugs, and clinicians discussed their use in the real-world setting.
In this video interview, – a liposome-encapsulated combination of daunorubicin and cytarabine approved in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, and midostaurin (Rydapt), which was approved in April for the treatment of newly diagnosed AML patients who are FLT3 mutation-positive. She also discussed future directions for these agents.
“So what clinicians are faced with is, all of a sudden, a number of new agents, and no particularly vetted or data-based algorithm by which to assign patients from one to the other,” said Dr. Michaelis, of the Medical College of Wisconsin, Milwaukee, adding that none of the drugs have been compared against one another.
In her own practice, when it comes to CPX-351, she said she first discusses the pros and cons with patients.
“This drug is used for older individuals ... with very adverse risk disease, and so the first question is do you fit the trial entry criteria, do you want to go through induction, do you understand what that’s going to mean, and am I going to take you to transplant after we go through this.”
As for midostaurin, she said she tries to use it on anyone who fits the trial criteria and is FLT-3 positive.
“The trick with that is that we don’t know the FLT-3 status at the time we have to start induction, so it’s hard to determine the exact right doses of your induction regimen knowing that you’re not going to get the test back until day 6, 7, 8, and you’re supposed to start delivering the drug on day 8, so we still have a ways as a care community to catch up with being able to give these drugs in a manner that was the same as what was delivered in the trials that led to approval.”
She also discussed the potential for combining treatments.
“I think there’s really room for studies on combinations of inhibitors plus the CPX, the safety of using a variety of induction regimens alongside midostaurin, and safety of combining things, like with midostaurin for example, with some of our antifungals ... and to make sure that that’s safe. So yeah, we’ve got a lot more to do,” she said.
Dr. Michaelis serves on an advisory board for Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – The past year brought a flurry of new drug approvals for the treatment of acute myeloid leukemia (AML), including CPX-351, midostaurin, gemtuzumab ozogamicin, and enasidenib.
During a special interest session at the annual meeting of the American Society of Hematology, Food and Drug Administration representatives discussed the available data and approval process for these drugs, and clinicians discussed their use in the real-world setting.
In this video interview, – a liposome-encapsulated combination of daunorubicin and cytarabine approved in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, and midostaurin (Rydapt), which was approved in April for the treatment of newly diagnosed AML patients who are FLT3 mutation-positive. She also discussed future directions for these agents.
“So what clinicians are faced with is, all of a sudden, a number of new agents, and no particularly vetted or data-based algorithm by which to assign patients from one to the other,” said Dr. Michaelis, of the Medical College of Wisconsin, Milwaukee, adding that none of the drugs have been compared against one another.
In her own practice, when it comes to CPX-351, she said she first discusses the pros and cons with patients.
“This drug is used for older individuals ... with very adverse risk disease, and so the first question is do you fit the trial entry criteria, do you want to go through induction, do you understand what that’s going to mean, and am I going to take you to transplant after we go through this.”
As for midostaurin, she said she tries to use it on anyone who fits the trial criteria and is FLT-3 positive.
“The trick with that is that we don’t know the FLT-3 status at the time we have to start induction, so it’s hard to determine the exact right doses of your induction regimen knowing that you’re not going to get the test back until day 6, 7, 8, and you’re supposed to start delivering the drug on day 8, so we still have a ways as a care community to catch up with being able to give these drugs in a manner that was the same as what was delivered in the trials that led to approval.”
She also discussed the potential for combining treatments.
“I think there’s really room for studies on combinations of inhibitors plus the CPX, the safety of using a variety of induction regimens alongside midostaurin, and safety of combining things, like with midostaurin for example, with some of our antifungals ... and to make sure that that’s safe. So yeah, we’ve got a lot more to do,” she said.
Dr. Michaelis serves on an advisory board for Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – The past year brought a flurry of new drug approvals for the treatment of acute myeloid leukemia (AML), including CPX-351, midostaurin, gemtuzumab ozogamicin, and enasidenib.
During a special interest session at the annual meeting of the American Society of Hematology, Food and Drug Administration representatives discussed the available data and approval process for these drugs, and clinicians discussed their use in the real-world setting.
In this video interview, – a liposome-encapsulated combination of daunorubicin and cytarabine approved in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, and midostaurin (Rydapt), which was approved in April for the treatment of newly diagnosed AML patients who are FLT3 mutation-positive. She also discussed future directions for these agents.
“So what clinicians are faced with is, all of a sudden, a number of new agents, and no particularly vetted or data-based algorithm by which to assign patients from one to the other,” said Dr. Michaelis, of the Medical College of Wisconsin, Milwaukee, adding that none of the drugs have been compared against one another.
In her own practice, when it comes to CPX-351, she said she first discusses the pros and cons with patients.
“This drug is used for older individuals ... with very adverse risk disease, and so the first question is do you fit the trial entry criteria, do you want to go through induction, do you understand what that’s going to mean, and am I going to take you to transplant after we go through this.”
As for midostaurin, she said she tries to use it on anyone who fits the trial criteria and is FLT-3 positive.
“The trick with that is that we don’t know the FLT-3 status at the time we have to start induction, so it’s hard to determine the exact right doses of your induction regimen knowing that you’re not going to get the test back until day 6, 7, 8, and you’re supposed to start delivering the drug on day 8, so we still have a ways as a care community to catch up with being able to give these drugs in a manner that was the same as what was delivered in the trials that led to approval.”
She also discussed the potential for combining treatments.
“I think there’s really room for studies on combinations of inhibitors plus the CPX, the safety of using a variety of induction regimens alongside midostaurin, and safety of combining things, like with midostaurin for example, with some of our antifungals ... and to make sure that that’s safe. So yeah, we’ve got a lot more to do,” she said.
Dr. Michaelis serves on an advisory board for Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM ASH 2017
