User login
Two activin receptor fusion proteins show promise in anemia
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.
Patients were a median age of 71, and 70% were male.
They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.
Sotatercept efficacy
The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.
Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.
Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.
Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.
Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.
Sotatercept safety
“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”
Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).
Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.
Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”
He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.
He presented the data as abstract 3251. The study was supported by Celgene Corporation. 
*One patient was excluded from the efficacy analysis due to a protocol violation.
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.
Patients were a median age of 71, and 70% were male.
They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.
Sotatercept efficacy
The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.
Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.
Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.
Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.
Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.
Sotatercept safety
“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”
Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).
Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.
Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”
He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.
He presented the data as abstract 3251. The study was supported by Celgene Corporation.
*One patient was excluded from the efficacy analysis due to a protocol violation.
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.
Patients were a median age of 71, and 70% were male.
They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.
Sotatercept efficacy
The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.
Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.
Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.
Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.
Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.
Sotatercept safety
“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”
Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).
Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.
Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”
He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.
He presented the data as abstract 3251. The study was supported by Celgene Corporation.
*One patient was excluded from the efficacy analysis due to a protocol violation.
Discovery could help predict, prevent therapy-related AML
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.” 
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”
First randomized evidence for kinase inhibitor use in AML
Photo courtesy of ASH
SAN FRANCISCO—Researchers have presented the first randomized evidence that kinase inhibitors are effective in the treatment of acute myeloid leukemia
(AML).
The multikinase inhibitor sorafenib improved event-free and relapse-free survival in younger patients.
“Interestingly, at this point in time, we can see no clear overall survival benefit for patients treated in the sorafenib arm,” said trial investigator Christoph Röllig, MD, of the Universitätsklinikum Dresden in Germany.
Dr Röllig, representing the Study Alliance Leukemia, presented data on sorafenib from the SORAML trial during the plenary session of the 2014 ASH Annual Meeting (abstract 6). Some funding for this trial was provided by Bayer Healthcare, the company developing sorafenib.
Dr Röllig explained that support for sorafenib’s clinical efficacy in AML was based primarily on case series and a few early phase clinical and nonrandomized
trials.
An earlier randomized study with sorafenib in older AML patients showed no beneficial antileukemic effect with the addition of the agent, and the treatment was associated with significant morbidity.
However, because the biology of AML and drug tolerance are different in younger people, the Study Alliance Leukemia decided to test the drug in a younger
patient population.
They randomized 276 newly diagnosed AML patients aged 60 years or younger to receive 2 cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo.
The sorafenib dose was 800 mg per day orally. All patients received at least one dose of study medication, forming the statistical analysis set.
Once in complete remission, intermediate-risk patients with a family donor and high-risk patients with a matched donor went on to stem cell transplant.
All other patients proceeded to high-dose cytarabine-based consolidation treatment plus sorafenib or placebo followed by 1 year of maintenance treatment with sorafenib or placebo.
The primary endpoint was event-free survival (EFS). An event was defined as primary treatment failure, relapse, or death.
Patients in each arm were a median age of 50 years, 17% were FLT3-ITD positive, and 33% were NPM1 mutated.
The complete response (CR) rate was 60% in the sorafenib arm and 59% in the placebo arm. Patients with FLT3-ITD mutation achieved a 57% CR rate with sorafenib and a 52% CR rate with placebo.
After a median follow-up of 3 years, investigators observed “significant prolongation of event-free survival in the sorafenib arm,” Dr Röllig said.
Patients on the sorafenib arm had a median EFS of 40% compared with 22% on the placebo arm, or 21 months compared with 9 months (P=0.013).
Patients were censored at the time of transplant. However, uncensored results were very similar, Dr Röllig noted, “with an even greater advantage for sorafenib.”
Fifty-six percent of sorafenib-treated patients were relapse-free and alive after 3 years, compared with 38% of patients on placebo (P=0.017).
The 3-year overall survival was 63% in the sorafenib arm and 56% in the placebo arm (P=0.382).
An exploratory analysis of FLT3-ITD patients revealed that 1-year EFS for sorafenib-treated patients was 54%, and, for placebo-treated patients, it was 50%.
“The reasons for potential efficacy of sorafenib in this mainly FLT3-ITD-negative population must remain speculative,” Dr Röllig said. “We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.”
Sorafenib significantly increased the risk of grade 3 or greater hand-foot syndrome (P<0.001), diarrhea (P=0.001), bleeding (P=0.016), rash (P=0.045), liver toxicity (P=0.048), and fever (P=0.035).
Dr Röllig indicated a confirmatory trial would be desirable in order to establish sorafenib in the AML treatment armamentarium.
Photo courtesy of ASH
SAN FRANCISCO—Researchers have presented the first randomized evidence that kinase inhibitors are effective in the treatment of acute myeloid leukemia
(AML).
The multikinase inhibitor sorafenib improved event-free and relapse-free survival in younger patients.
“Interestingly, at this point in time, we can see no clear overall survival benefit for patients treated in the sorafenib arm,” said trial investigator Christoph Röllig, MD, of the Universitätsklinikum Dresden in Germany.
Dr Röllig, representing the Study Alliance Leukemia, presented data on sorafenib from the SORAML trial during the plenary session of the 2014 ASH Annual Meeting (abstract 6). Some funding for this trial was provided by Bayer Healthcare, the company developing sorafenib.
Dr Röllig explained that support for sorafenib’s clinical efficacy in AML was based primarily on case series and a few early phase clinical and nonrandomized
trials.
An earlier randomized study with sorafenib in older AML patients showed no beneficial antileukemic effect with the addition of the agent, and the treatment was associated with significant morbidity.
However, because the biology of AML and drug tolerance are different in younger people, the Study Alliance Leukemia decided to test the drug in a younger
patient population.
They randomized 276 newly diagnosed AML patients aged 60 years or younger to receive 2 cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo.
The sorafenib dose was 800 mg per day orally. All patients received at least one dose of study medication, forming the statistical analysis set.
Once in complete remission, intermediate-risk patients with a family donor and high-risk patients with a matched donor went on to stem cell transplant.
All other patients proceeded to high-dose cytarabine-based consolidation treatment plus sorafenib or placebo followed by 1 year of maintenance treatment with sorafenib or placebo.
The primary endpoint was event-free survival (EFS). An event was defined as primary treatment failure, relapse, or death.
Patients in each arm were a median age of 50 years, 17% were FLT3-ITD positive, and 33% were NPM1 mutated.
The complete response (CR) rate was 60% in the sorafenib arm and 59% in the placebo arm. Patients with FLT3-ITD mutation achieved a 57% CR rate with sorafenib and a 52% CR rate with placebo.
After a median follow-up of 3 years, investigators observed “significant prolongation of event-free survival in the sorafenib arm,” Dr Röllig said.
Patients on the sorafenib arm had a median EFS of 40% compared with 22% on the placebo arm, or 21 months compared with 9 months (P=0.013).
Patients were censored at the time of transplant. However, uncensored results were very similar, Dr Röllig noted, “with an even greater advantage for sorafenib.”
Fifty-six percent of sorafenib-treated patients were relapse-free and alive after 3 years, compared with 38% of patients on placebo (P=0.017).
The 3-year overall survival was 63% in the sorafenib arm and 56% in the placebo arm (P=0.382).
An exploratory analysis of FLT3-ITD patients revealed that 1-year EFS for sorafenib-treated patients was 54%, and, for placebo-treated patients, it was 50%.
“The reasons for potential efficacy of sorafenib in this mainly FLT3-ITD-negative population must remain speculative,” Dr Röllig said. “We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.”
Sorafenib significantly increased the risk of grade 3 or greater hand-foot syndrome (P<0.001), diarrhea (P=0.001), bleeding (P=0.016), rash (P=0.045), liver toxicity (P=0.048), and fever (P=0.035).
Dr Röllig indicated a confirmatory trial would be desirable in order to establish sorafenib in the AML treatment armamentarium.
Photo courtesy of ASH
SAN FRANCISCO—Researchers have presented the first randomized evidence that kinase inhibitors are effective in the treatment of acute myeloid leukemia
(AML).
The multikinase inhibitor sorafenib improved event-free and relapse-free survival in younger patients.
“Interestingly, at this point in time, we can see no clear overall survival benefit for patients treated in the sorafenib arm,” said trial investigator Christoph Röllig, MD, of the Universitätsklinikum Dresden in Germany.
Dr Röllig, representing the Study Alliance Leukemia, presented data on sorafenib from the SORAML trial during the plenary session of the 2014 ASH Annual Meeting (abstract 6). Some funding for this trial was provided by Bayer Healthcare, the company developing sorafenib.
Dr Röllig explained that support for sorafenib’s clinical efficacy in AML was based primarily on case series and a few early phase clinical and nonrandomized
trials.
An earlier randomized study with sorafenib in older AML patients showed no beneficial antileukemic effect with the addition of the agent, and the treatment was associated with significant morbidity.
However, because the biology of AML and drug tolerance are different in younger people, the Study Alliance Leukemia decided to test the drug in a younger
patient population.
They randomized 276 newly diagnosed AML patients aged 60 years or younger to receive 2 cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo.
The sorafenib dose was 800 mg per day orally. All patients received at least one dose of study medication, forming the statistical analysis set.
Once in complete remission, intermediate-risk patients with a family donor and high-risk patients with a matched donor went on to stem cell transplant.
All other patients proceeded to high-dose cytarabine-based consolidation treatment plus sorafenib or placebo followed by 1 year of maintenance treatment with sorafenib or placebo.
The primary endpoint was event-free survival (EFS). An event was defined as primary treatment failure, relapse, or death.
Patients in each arm were a median age of 50 years, 17% were FLT3-ITD positive, and 33% were NPM1 mutated.
The complete response (CR) rate was 60% in the sorafenib arm and 59% in the placebo arm. Patients with FLT3-ITD mutation achieved a 57% CR rate with sorafenib and a 52% CR rate with placebo.
After a median follow-up of 3 years, investigators observed “significant prolongation of event-free survival in the sorafenib arm,” Dr Röllig said.
Patients on the sorafenib arm had a median EFS of 40% compared with 22% on the placebo arm, or 21 months compared with 9 months (P=0.013).
Patients were censored at the time of transplant. However, uncensored results were very similar, Dr Röllig noted, “with an even greater advantage for sorafenib.”
Fifty-six percent of sorafenib-treated patients were relapse-free and alive after 3 years, compared with 38% of patients on placebo (P=0.017).
The 3-year overall survival was 63% in the sorafenib arm and 56% in the placebo arm (P=0.382).
An exploratory analysis of FLT3-ITD patients revealed that 1-year EFS for sorafenib-treated patients was 54%, and, for placebo-treated patients, it was 50%.
“The reasons for potential efficacy of sorafenib in this mainly FLT3-ITD-negative population must remain speculative,” Dr Röllig said. “We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.”
Sorafenib significantly increased the risk of grade 3 or greater hand-foot syndrome (P<0.001), diarrhea (P=0.001), bleeding (P=0.016), rash (P=0.045), liver toxicity (P=0.048), and fever (P=0.035).
Dr Röllig indicated a confirmatory trial would be desirable in order to establish sorafenib in the AML treatment armamentarium.
FDA approves drug for HCM
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.
The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.
Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).
The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.
The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.
Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).
The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.
The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.
Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).
The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
Targeted Therapy for Chronic Lymphocytic Leukemia
This presentation by Adrian Wiestner, MD, PhD, from the 2014 AVAHO Meeting in Portland, Oregon, provides an overview of new insights into the pathogenesis and treatment of CLL, how to interpret molecular targets during treatment, and the advantages and disadvantages of these treatment options for patients.
"The standard of care today is really chemo-immunotherapy," Wiestner said. "Ideally, we would like to have a more disease-directed therapy that is tolerable and active."
This presentation by Adrian Wiestner, MD, PhD, from the 2014 AVAHO Meeting in Portland, Oregon, provides an overview of new insights into the pathogenesis and treatment of CLL, how to interpret molecular targets during treatment, and the advantages and disadvantages of these treatment options for patients.
"The standard of care today is really chemo-immunotherapy," Wiestner said. "Ideally, we would like to have a more disease-directed therapy that is tolerable and active."
This presentation by Adrian Wiestner, MD, PhD, from the 2014 AVAHO Meeting in Portland, Oregon, provides an overview of new insights into the pathogenesis and treatment of CLL, how to interpret molecular targets during treatment, and the advantages and disadvantages of these treatment options for patients.
"The standard of care today is really chemo-immunotherapy," Wiestner said. "Ideally, we would like to have a more disease-directed therapy that is tolerable and active."
More isn’t always better with daunorubicin induction in AML
Photo courtesy of ASH
SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.
And a 90 mg/m2 dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m2 compared to 90.
Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.
He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.
The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.
The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.
And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.
So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.
The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m2 on days 1, 3, and 5 in course 2.
All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.
The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.
The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.
Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.
The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.
However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).
Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.
The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.
At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.
The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.
One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.
When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.
The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m2 in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.
FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).
Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.
Photo courtesy of ASH
SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.
And a 90 mg/m2 dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m2 compared to 90.
Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.
He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.
The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.
The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.
And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.
So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.
The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m2 on days 1, 3, and 5 in course 2.
All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.
The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.
The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.
Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.
The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.
However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).
Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.
The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.
At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.
The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.
One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.
When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.
The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m2 in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.
FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).
Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.
Photo courtesy of ASH
SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.
And a 90 mg/m2 dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m2 compared to 90.
Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.
He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.
The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.
The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.
And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.
So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.
The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m2 on days 1, 3, and 5 in course 2.
All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.
The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.
The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.
Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.
The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.
However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).
Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.
The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.
At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.
The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.
One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.
When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.
The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m2 in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.
FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).
Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.
Encapsulating doxorubicin can reduce heart damage
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Disordered methylation compromises CLL treatment
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
CLL drug can fight AML too, study suggests
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Finding could help docs tailor treatment for myeloid leukemias
PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.
Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.
The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.
The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).
Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.
But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.
The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.
They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.
Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.
By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.
The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.
They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.
They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.
PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.
Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.
The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.
The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).
Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.
But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.
The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.
They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.
Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.
By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.
The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.
They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.
They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.
PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.
Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.
The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.
The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).
Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.
But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.
The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.
They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.
Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.
By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.
The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.
They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.
They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.