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DNA methylation may predict outcomes in JMML
New research suggests DNA methylation may be used to predict how children with juvenile myelomonocytic leukemia (JMML) will respond to treatment.
Researchers found they could divide patients into risk groups according to their methylation levels.
Patients with the highest methylation levels had the worst event-free survival, while patients who recovered spontaneously had methylation levels similar to those of healthy control subjects.
“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said Mignon Loh, MD, of Benioff Children’s Hospital, University of California, San Francisco.
She and her colleagues described this research in Nature Communications.
The team studied genome-wide DNA methylation levels in an initial group of 39 patients with JMML and then validated the results in a group of 40 JMML patients.
Statistical analysis revealed that patients fell into 3 clusters with high, intermediate, or low levels of DNA methylation. And patients’ methylation levels were associated with 4-year event-free survival.
In the initial cohort, 6% (1/15) of patients in the lowest methylation group had an event at 4 years, as did 45% (5/11) of patients with intermediate levels of methylation and 61% (8/13) of patients with the highest levels of methylation.
In the validation cohort, 8% (1/12) of patients in the lowest methylation group had an event at 4 years, as did 36% (4/11) of patients with intermediate levels of methylation and 76% (13/17) of patients with the highest levels of methylation.
“For us, this was surprising,” said study author Elliot Stieglitz, MD, also of Benioff Children’s Hospital.
“We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise.”
The researchers also found that methylation levels might predict spontaneous remission as well.
Thirteen of the 14 patients who had spontaneous remission clustered together. And their DNA methylation levels were closer to those of healthy control subjects than those of other JMML cases.
“Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody,” Dr Stieglitz said.
“There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science.” 
New research suggests DNA methylation may be used to predict how children with juvenile myelomonocytic leukemia (JMML) will respond to treatment.
Researchers found they could divide patients into risk groups according to their methylation levels.
Patients with the highest methylation levels had the worst event-free survival, while patients who recovered spontaneously had methylation levels similar to those of healthy control subjects.
“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said Mignon Loh, MD, of Benioff Children’s Hospital, University of California, San Francisco.
She and her colleagues described this research in Nature Communications.
The team studied genome-wide DNA methylation levels in an initial group of 39 patients with JMML and then validated the results in a group of 40 JMML patients.
Statistical analysis revealed that patients fell into 3 clusters with high, intermediate, or low levels of DNA methylation. And patients’ methylation levels were associated with 4-year event-free survival.
In the initial cohort, 6% (1/15) of patients in the lowest methylation group had an event at 4 years, as did 45% (5/11) of patients with intermediate levels of methylation and 61% (8/13) of patients with the highest levels of methylation.
In the validation cohort, 8% (1/12) of patients in the lowest methylation group had an event at 4 years, as did 36% (4/11) of patients with intermediate levels of methylation and 76% (13/17) of patients with the highest levels of methylation.
“For us, this was surprising,” said study author Elliot Stieglitz, MD, also of Benioff Children’s Hospital.
“We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise.”
The researchers also found that methylation levels might predict spontaneous remission as well.
Thirteen of the 14 patients who had spontaneous remission clustered together. And their DNA methylation levels were closer to those of healthy control subjects than those of other JMML cases.
“Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody,” Dr Stieglitz said.
“There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science.”
New research suggests DNA methylation may be used to predict how children with juvenile myelomonocytic leukemia (JMML) will respond to treatment.
Researchers found they could divide patients into risk groups according to their methylation levels.
Patients with the highest methylation levels had the worst event-free survival, while patients who recovered spontaneously had methylation levels similar to those of healthy control subjects.
“This data provides important information that will help clinicians decide how intensively and swiftly to treat their patients,” said Mignon Loh, MD, of Benioff Children’s Hospital, University of California, San Francisco.
She and her colleagues described this research in Nature Communications.
The team studied genome-wide DNA methylation levels in an initial group of 39 patients with JMML and then validated the results in a group of 40 JMML patients.
Statistical analysis revealed that patients fell into 3 clusters with high, intermediate, or low levels of DNA methylation. And patients’ methylation levels were associated with 4-year event-free survival.
In the initial cohort, 6% (1/15) of patients in the lowest methylation group had an event at 4 years, as did 45% (5/11) of patients with intermediate levels of methylation and 61% (8/13) of patients with the highest levels of methylation.
In the validation cohort, 8% (1/12) of patients in the lowest methylation group had an event at 4 years, as did 36% (4/11) of patients with intermediate levels of methylation and 76% (13/17) of patients with the highest levels of methylation.
“For us, this was surprising,” said study author Elliot Stieglitz, MD, also of Benioff Children’s Hospital.
“We are not yet able to say why DNA methylation is different amongst these patients, but for it to be so predictive of outcomes, even more than genetic mutations, was a big surprise.”
The researchers also found that methylation levels might predict spontaneous remission as well.
Thirteen of the 14 patients who had spontaneous remission clustered together. And their DNA methylation levels were closer to those of healthy control subjects than those of other JMML cases.
“Because we have never been able to tell which patients might spontaneously recover, and because the disease can be so aggressive, the standard of care has been to recommend transplants for everybody,” Dr Stieglitz said.
“There are many health risks associated with bone marrow transplants, ranging from infections to long-term short stature and even death in some cases. To be able to avoid this intensive intervention for some patients based on a methylation assay would really be cutting-edge clinical science.”
Gene variants associated with high-risk pediatric ALL
New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.
Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.
These variants were associated with inferior survival and an increased risk of developing second malignancies.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.
The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).
The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.
The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).
Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).
The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).
The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.
And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).
“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”
The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.
“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”
Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.
“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”
New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.
Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.
These variants were associated with inferior survival and an increased risk of developing second malignancies.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.
The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).
The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.
The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).
Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).
The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).
The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.
And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).
“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”
The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.
“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”
Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.
“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”
New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.
Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.
These variants were associated with inferior survival and an increased risk of developing second malignancies.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.
The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).
The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.
The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).
Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).
The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).
The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.
And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).
“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”
The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.
“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”
Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.
“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”
Method prolongs lifespan of blood samples
A new blood stabilization method significantly prolongs the lifespan of blood samples for microfluidic sorting and transcriptome profiling of rare circulating tumor cells (CTCs), according to researchers.
The method involves reducing the storage temperature to 4° C to reversibly slow down cellular processes while also counteracting the platelet activation that can occur because of the low temperature.
The researchers said this work overcomes a significant barrier to the translation of liquid biopsy technologies for precision oncology and other applications.
Keith Wong, PhD, of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM), and his colleagues described this work in Nature Communications.
When isolating CTCs from fresh, unprocessed blood, timing is everything. Even minor changes in the quality of a blood sample—such as the breakdown of red cells, leukocyte activation, or clot formation— can greatly affect cell-sorting mechanisms and the quality of the biomolecules isolated for cancer detection.
According to published studies, factors such as the total number of CTCs in a sample and the number with high-quality RNA decrease by around 50% within the first 4 to 5 hours after the sample is collected.
“At Mass. General, we have the luxury of being so integrated with the clinical team that we can process blood specimens in the lab typically within an hour or 2 after they are drawn,” Dr Wong said.
“But to make these liquid biopsy technologies routine lab tests for the rest of the world, we need ways to keep blood alive for much longer than several hours, since these assays are best performed in central laboratories for reasons of cost-effectiveness and reproducibility.”
With this in mind, Dr Wong and his colleagues set out to preserve blood in its native state with minimal alterations.
“We wanted to slow down the biological clock as much as possible by using hypothermia, but that is not as simple as it sounds,” said study author Shannon Tessier, PhD, also of MGH-CEM.
“Low temperature is a powerful means to decrease metabolism, but a host of unwanted side effects occur at the same time. In some ways, these challenges are similar to those we face in organ preservation, where we have to optimize strategies for a very complex mix of cells.”
To achieve these goals, the researchers first analyzed the effects of hypothermic storage conditions.
The team found that hypothermic storage (4° C) of blood anticoagulated with acid citrate dextrose maintained “cellular morphology, integrity, and surface epitope stability of diverse hematologic cell types” over 72 hours.
However, the researchers also observed platelet activation.
“We are preserving the blood very well, including the coagulation function of platelets,” Dr Wong said. “But, unfortunately, cooling causes profound activation of platelets. Now, we need a targeted approach for platelets so they don’t form nasty clots in the microfluidic blood-sorting device.”
Fortunately, the researchers found that glycoprotein IIb/IIIa inhibitors were able to counter cooling-induced platelet aggregation. And ion chelation treatment with ethylenediaminetetraacetic acid removed activated platelets from leukocytes.
The team said these steps—hypothermic storage, treatment with glycoprotein IIb/IIIa inhibitors, and ion chelation—allowed whole blood preserved for 3 days to be processed as if it were freshly drawn, with very high purity and virtually no loss in CTC numbers.
“The critical achievement here is that the isolated tumor cells contain high-quality RNA that is suitable for demanding molecular assays, such as single-cell qPCR, droplet digital PCR, and RNA sequencing,” Dr Tessier said.
To test their blood preservation method, Dr Tessier and her colleagues used blood specimens from a group of 10 patients with metastatic prostate cancer.
The researchers compared CTC analysis in preserved blood samples and paired fresh samples from the same patients.
There was 92% agreement in the detection of 12 cancer-specific gene transcripts between the fresh and preserved blood samples.
In addition, there was 100% agreement in the detection of a transcript called AR-V7. Recently published studies showed that the presence of AR-V7 mRNA in prostate cancer CTCs predicts resistance to androgen receptor inhibitors, indicating that chemotherapy may be a better option for such patients.
“The ability to preserve the blood for several days and still be able to pick up this clinically relevant biomarker is remarkable,” said study author David Miyamoto, MD, PhD, of MGH Cancer Center.
“This is very exciting for clinicians because AR-V7 mRNA can only be detected using CTCs and not with circulating tumor DNA or other cell-free assays.”
The researchers highlighted the universal nature of their blood preservation approach by pointing to its compatibility with the microfluidic CTC-iChip device, which isolates tumor cells by rapid removal of blood cells. The team said this suggests the potential impact of this work extends beyond cancer detection.
“With exciting breakthroughs in immunotherapy, stem cell transplantation, and regenerative medicine—in which peripheral blood is often the source of cells for functional assays or ex vivo expansion—the ability to preserve live cells will greatly ease logistical timelines and reduce the cost of complex cell-based assays,” Dr Wong said.
A new blood stabilization method significantly prolongs the lifespan of blood samples for microfluidic sorting and transcriptome profiling of rare circulating tumor cells (CTCs), according to researchers.
The method involves reducing the storage temperature to 4° C to reversibly slow down cellular processes while also counteracting the platelet activation that can occur because of the low temperature.
The researchers said this work overcomes a significant barrier to the translation of liquid biopsy technologies for precision oncology and other applications.
Keith Wong, PhD, of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM), and his colleagues described this work in Nature Communications.
When isolating CTCs from fresh, unprocessed blood, timing is everything. Even minor changes in the quality of a blood sample—such as the breakdown of red cells, leukocyte activation, or clot formation— can greatly affect cell-sorting mechanisms and the quality of the biomolecules isolated for cancer detection.
According to published studies, factors such as the total number of CTCs in a sample and the number with high-quality RNA decrease by around 50% within the first 4 to 5 hours after the sample is collected.
“At Mass. General, we have the luxury of being so integrated with the clinical team that we can process blood specimens in the lab typically within an hour or 2 after they are drawn,” Dr Wong said.
“But to make these liquid biopsy technologies routine lab tests for the rest of the world, we need ways to keep blood alive for much longer than several hours, since these assays are best performed in central laboratories for reasons of cost-effectiveness and reproducibility.”
With this in mind, Dr Wong and his colleagues set out to preserve blood in its native state with minimal alterations.
“We wanted to slow down the biological clock as much as possible by using hypothermia, but that is not as simple as it sounds,” said study author Shannon Tessier, PhD, also of MGH-CEM.
“Low temperature is a powerful means to decrease metabolism, but a host of unwanted side effects occur at the same time. In some ways, these challenges are similar to those we face in organ preservation, where we have to optimize strategies for a very complex mix of cells.”
To achieve these goals, the researchers first analyzed the effects of hypothermic storage conditions.
The team found that hypothermic storage (4° C) of blood anticoagulated with acid citrate dextrose maintained “cellular morphology, integrity, and surface epitope stability of diverse hematologic cell types” over 72 hours.
However, the researchers also observed platelet activation.
“We are preserving the blood very well, including the coagulation function of platelets,” Dr Wong said. “But, unfortunately, cooling causes profound activation of platelets. Now, we need a targeted approach for platelets so they don’t form nasty clots in the microfluidic blood-sorting device.”
Fortunately, the researchers found that glycoprotein IIb/IIIa inhibitors were able to counter cooling-induced platelet aggregation. And ion chelation treatment with ethylenediaminetetraacetic acid removed activated platelets from leukocytes.
The team said these steps—hypothermic storage, treatment with glycoprotein IIb/IIIa inhibitors, and ion chelation—allowed whole blood preserved for 3 days to be processed as if it were freshly drawn, with very high purity and virtually no loss in CTC numbers.
“The critical achievement here is that the isolated tumor cells contain high-quality RNA that is suitable for demanding molecular assays, such as single-cell qPCR, droplet digital PCR, and RNA sequencing,” Dr Tessier said.
To test their blood preservation method, Dr Tessier and her colleagues used blood specimens from a group of 10 patients with metastatic prostate cancer.
The researchers compared CTC analysis in preserved blood samples and paired fresh samples from the same patients.
There was 92% agreement in the detection of 12 cancer-specific gene transcripts between the fresh and preserved blood samples.
In addition, there was 100% agreement in the detection of a transcript called AR-V7. Recently published studies showed that the presence of AR-V7 mRNA in prostate cancer CTCs predicts resistance to androgen receptor inhibitors, indicating that chemotherapy may be a better option for such patients.
“The ability to preserve the blood for several days and still be able to pick up this clinically relevant biomarker is remarkable,” said study author David Miyamoto, MD, PhD, of MGH Cancer Center.
“This is very exciting for clinicians because AR-V7 mRNA can only be detected using CTCs and not with circulating tumor DNA or other cell-free assays.”
The researchers highlighted the universal nature of their blood preservation approach by pointing to its compatibility with the microfluidic CTC-iChip device, which isolates tumor cells by rapid removal of blood cells. The team said this suggests the potential impact of this work extends beyond cancer detection.
“With exciting breakthroughs in immunotherapy, stem cell transplantation, and regenerative medicine—in which peripheral blood is often the source of cells for functional assays or ex vivo expansion—the ability to preserve live cells will greatly ease logistical timelines and reduce the cost of complex cell-based assays,” Dr Wong said.
A new blood stabilization method significantly prolongs the lifespan of blood samples for microfluidic sorting and transcriptome profiling of rare circulating tumor cells (CTCs), according to researchers.
The method involves reducing the storage temperature to 4° C to reversibly slow down cellular processes while also counteracting the platelet activation that can occur because of the low temperature.
The researchers said this work overcomes a significant barrier to the translation of liquid biopsy technologies for precision oncology and other applications.
Keith Wong, PhD, of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM), and his colleagues described this work in Nature Communications.
When isolating CTCs from fresh, unprocessed blood, timing is everything. Even minor changes in the quality of a blood sample—such as the breakdown of red cells, leukocyte activation, or clot formation— can greatly affect cell-sorting mechanisms and the quality of the biomolecules isolated for cancer detection.
According to published studies, factors such as the total number of CTCs in a sample and the number with high-quality RNA decrease by around 50% within the first 4 to 5 hours after the sample is collected.
“At Mass. General, we have the luxury of being so integrated with the clinical team that we can process blood specimens in the lab typically within an hour or 2 after they are drawn,” Dr Wong said.
“But to make these liquid biopsy technologies routine lab tests for the rest of the world, we need ways to keep blood alive for much longer than several hours, since these assays are best performed in central laboratories for reasons of cost-effectiveness and reproducibility.”
With this in mind, Dr Wong and his colleagues set out to preserve blood in its native state with minimal alterations.
“We wanted to slow down the biological clock as much as possible by using hypothermia, but that is not as simple as it sounds,” said study author Shannon Tessier, PhD, also of MGH-CEM.
“Low temperature is a powerful means to decrease metabolism, but a host of unwanted side effects occur at the same time. In some ways, these challenges are similar to those we face in organ preservation, where we have to optimize strategies for a very complex mix of cells.”
To achieve these goals, the researchers first analyzed the effects of hypothermic storage conditions.
The team found that hypothermic storage (4° C) of blood anticoagulated with acid citrate dextrose maintained “cellular morphology, integrity, and surface epitope stability of diverse hematologic cell types” over 72 hours.
However, the researchers also observed platelet activation.
“We are preserving the blood very well, including the coagulation function of platelets,” Dr Wong said. “But, unfortunately, cooling causes profound activation of platelets. Now, we need a targeted approach for platelets so they don’t form nasty clots in the microfluidic blood-sorting device.”
Fortunately, the researchers found that glycoprotein IIb/IIIa inhibitors were able to counter cooling-induced platelet aggregation. And ion chelation treatment with ethylenediaminetetraacetic acid removed activated platelets from leukocytes.
The team said these steps—hypothermic storage, treatment with glycoprotein IIb/IIIa inhibitors, and ion chelation—allowed whole blood preserved for 3 days to be processed as if it were freshly drawn, with very high purity and virtually no loss in CTC numbers.
“The critical achievement here is that the isolated tumor cells contain high-quality RNA that is suitable for demanding molecular assays, such as single-cell qPCR, droplet digital PCR, and RNA sequencing,” Dr Tessier said.
To test their blood preservation method, Dr Tessier and her colleagues used blood specimens from a group of 10 patients with metastatic prostate cancer.
The researchers compared CTC analysis in preserved blood samples and paired fresh samples from the same patients.
There was 92% agreement in the detection of 12 cancer-specific gene transcripts between the fresh and preserved blood samples.
In addition, there was 100% agreement in the detection of a transcript called AR-V7. Recently published studies showed that the presence of AR-V7 mRNA in prostate cancer CTCs predicts resistance to androgen receptor inhibitors, indicating that chemotherapy may be a better option for such patients.
“The ability to preserve the blood for several days and still be able to pick up this clinically relevant biomarker is remarkable,” said study author David Miyamoto, MD, PhD, of MGH Cancer Center.
“This is very exciting for clinicians because AR-V7 mRNA can only be detected using CTCs and not with circulating tumor DNA or other cell-free assays.”
The researchers highlighted the universal nature of their blood preservation approach by pointing to its compatibility with the microfluidic CTC-iChip device, which isolates tumor cells by rapid removal of blood cells. The team said this suggests the potential impact of this work extends beyond cancer detection.
“With exciting breakthroughs in immunotherapy, stem cell transplantation, and regenerative medicine—in which peripheral blood is often the source of cells for functional assays or ex vivo expansion—the ability to preserve live cells will greatly ease logistical timelines and reduce the cost of complex cell-based assays,” Dr Wong said.
Drug receives breakthrough designation for SCD
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).
Voxelotor is being developed by Global Blood Therapeutics, Inc., as a potentially disease-modifying therapy for SCD.
The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that voxelotor blocks polymerization and the resultant sickling of red blood cells.
If voxelotor can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.
The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.
The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:
- Part A of the phase 3 HOPE study (GBT440-031)
- A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
- The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
- The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).
Voxelotor is being developed by Global Blood Therapeutics, Inc., as a potentially disease-modifying therapy for SCD.
The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that voxelotor blocks polymerization and the resultant sickling of red blood cells.
If voxelotor can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.
The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.
The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:
- Part A of the phase 3 HOPE study (GBT440-031)
- A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
- The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
- The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).
Voxelotor is being developed by Global Blood Therapeutics, Inc., as a potentially disease-modifying therapy for SCD.
The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that voxelotor blocks polymerization and the resultant sickling of red blood cells.
If voxelotor can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.
The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.
The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:
- Part A of the phase 3 HOPE study (GBT440-031)
- A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
- The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
- The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Team finds way to target MYB in AML
Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”
Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”
Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”
Update of gene therapy in hemophilia A
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
ATLANTA—Updated trial results have shown that gene therapy can increase factor VIII (FVIII) levels and reduce the need for FVIII infusions in patients with severe hemophilia A.
Most patients who received the gene therapy, valoctocogene roxaparvovec (VR, formerly BMN 270), were able to achieve normal or near-normal FVIII levels.
In addition, patients were able to discontinue prophylactic FVIII infusions and greatly reduce the number of on-demand FVIII infusions they received.
“We have seen mind-blowing results, which have far exceeded our expectations,” said study investigator K. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“When we started out, we thought it would be a huge achievement to show a 5% improvement [in FVIII levels], so to actually be seeing normal or near-normal factor levels with dramatic reduction in bleeding is, quite simply, amazing.”
Dr Pasi presented these results—with 1.5 years of follow-up—at the 2017 ASH Annual Meeting (abstract 603*).
One-year results from this phase 1/2 trial were simultaneously published in NEJM. Previous results were reported at the ISTH 2017 Congress.
The trial was sponsored by BioMarin Pharmaceuticals, Inc., the company developing VR.
The trial included 13 patients with previously treated, severe hemophilia A (defined as less than or equal to 1% of FVIII activity levels, expressed as a percentage of normal factor activity in blood).
Seven of the patients received VR at a 6e13 vg/kg dose, and 6 received VR at a 4e13 vg/kg dose.
The data presented at ASH had a cutoff date of November 16, 2017.
4e13 vg/kg-dose group
All 6 patients in the 4e13 vg/kg-dose group had 36 weeks of follow-up. At that point, the median FVIII level for the group was 38%, and the mean was 35% (range, 4-55).
For the 3 patients who had 48 weeks of follow-up, the median and mean FVIII levels were both 49% (range, 38-60).
Before receiving VR, these patients (all 6) had a median annualized bleeding rate (ABR) of 8.0 and a mean ABR of 12.2.
Four weeks after receiving VR, the median ABR was 0.0 and the mean ABR was 0.6.
Before receiving VR, each patient received a median of 155.5 FVIII infusions per year and a mean of 146.5 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean of 2.0 FVIII infusions.
6e13 vg/kg-dose group
All 7 patients in this group had at least 78 weeks of follow-up. At this point, the median FVIII level for the group was 90%, and the mean was 89% (range, 11-179).
One patient received on-demand FVIII treatment while on study and was excluded from the analysis of ABR and FVIII infusions.
The remaining 6 patients, before VR, had a median ABR of 16.5 and a mean ABR of 16.3.
Four weeks after VR infusion, the median ABR was 0.0, and the mean was 0.5.
Before receiving VR, each patient received a median of 138.5 FVIII infusions per year and a mean 136.7 FVIII infusions.
Four weeks after receiving VR, they received a median of 0.0 FVIII infusions and mean 6.1 FVIII infusions.
Five patients had 0 bleeds requiring FVIII infusions and 0 FVIII infusions from week 4 after VR infusion until last follow-up.
“The clinical data, to date, for this investigational gene therapy exceeded our expectations, in terms of increasing FVIII levels and reducing the annualized bleed rate,” Dr Pasi said.
“Many clinical trial participants have seen FVIII levels at or close to normal. With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”
Safety
The safety data included 2 patients who received VR at 6e12 vg/kg and 2e13 vg/kg, respectively, as well as the 13 patients for whom efficacy data were reported at ASH.
None of the patients developed inhibitors to FVIII, and none withdrew from the study.
The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase elevation (n=11, 73%), arthralgia (n=9, 60%), aspartate aminotransferase elevation (n=8, 53%), headache (n=7, 47%), back pain (n=5, 33%), fatigue (n=5, 33%), and upper respiratory tract infection (n=5, 33%).
Serious AEs were reported in 2 patients. One of these events was considered related to VR.
The patient with the VR-related serious AE was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving VR. The event resolved within 48 hours of treatment with paracetamol.
The other serious AE was attributed to a planned knee surgery to treat hemophilic arthropathy, and it was grade 1 in severity. No complications were reported.
*Data in the presentation differ from the abstract.
Overcoming resistance to ibrutinib in CLL
New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).
It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.
But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.
Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.
The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.
These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.
With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.
Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.
The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.
The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.
“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.
“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”
Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.
The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.
Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”
The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.
“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.
New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).
It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.
But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.
Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.
The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.
These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.
With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.
Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.
The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.
The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.
“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.
“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”
Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.
The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.
Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”
The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.
“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.
New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).
It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.
But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.
Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.
The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.
These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.
With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.
Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.
The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.
The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.
“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.
“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”
Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.
The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.
Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”
The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.
“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.
Antiviral receives breakthrough designation for CMV
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA approves denosumab for MM patients
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
Drug granted breakthrough status as first-line SAA therapy
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).
Novartis plans to submit an application to the FDA for this indication later this year.
Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.
The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.
Trial data
The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.
The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.
Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.
At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.
At a median follow-up of 2 years, the overall survival rate was 97%.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.
There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).
Novartis plans to submit an application to the FDA for this indication later this year.
Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.
The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.
Trial data
The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.
The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.
Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.
At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.
At a median follow-up of 2 years, the overall survival rate was 97%.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.
There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).
Novartis plans to submit an application to the FDA for this indication later this year.
Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.
The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.
Trial data
The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.
The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.
Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.
At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.
At a median follow-up of 2 years, the overall survival rate was 97%.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.
There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.