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NCCN releases guidelines for managing MF
The National Comprehensive Cancer Network (NCCN) has published new clinical practice guidelines for myeloproliferative neoplasms (MPNs).
The current guidelines focus on the management of patients with myelofibrosis (MF), but NCCN said recommendations for managing essential thrombocythemia (ET) and polycythemia vera (PV) will be included in subsequent versions of the NCCN guidelines for MPNs.
The new guidelines provide recommendations on the workup and diagnosis of primary MF, post-ET MF, and post-PV MF.
The document also includes recommendations for managing MF-associated anemia, supportive care options, and treatment recommendations according to a patient’s risk group.
Treatment of low-risk MF
The guidelines recommend that patients with low-risk, asymptomatic MF be observed or enrolled in a clinical trial. They should be monitored for progression every 3 to 6 months.
Patients with low-risk, symptomatic MF should receive ruxolitinib or interferons or be enrolled on a clinical trial. They should be monitored for progression every 3 to 6 months.
If patients respond to treatment, they should continue to receive it. If they do not respond or lose their response, they should receive ruxolitinib or interferons or be enrolled on a clinical trial. If these patients progress, they should be treated according to their risk category.
Intermediate-1-risk MF
Patients with intermediate-1-risk MF should be assessed for symptom burden and observed if asymptomatic. If symptomatic, they should receive ruxolitinib, be enrolled on a clinical trial, or undergo allogeneic hematopoietic stem cell transplant (HSCT).
Patients should be monitored for response and progression every 3 to 6 months. If they respond to treatment, they should continue to receive it.
If patients do not respond or lose their response, they should be observed, receive ruxolitinib, be enrolled on a clinical trial, or undergo allogeneic HSCT. If these patients progress, they should be treated according to their risk category.
Intermediate-2- or high-risk MF
Patients who are transplant candidates should receive allogeneic HSCT.
Patients who are ineligible for transplant should be assessed for symptom burden. Those with a platelet count of 50,000 or lower should be considered for a clinical trial.
Those with higher platelet counts should receive ruxolitinib or be enrolled on a clinical trial. They should be monitored for response or progression every 3 to 6 months.
If these patients respond to treatment, they should continue on that treatment. If they do not respond or lose their response, the patients should be monitored for progression.
If they progress and are candidates for transplant, these patients should receive hypomethylating agents or chemotherapy to induce remission, followed by HSCT.
If the patients progress and are ineligible for transplant, they should be enrolled on a clinical trial or receive hypomethylating agents or chemotherapy.
For patients who are ineligible for transplant and only have symptomatic anemia, they should receive treatment to manage that anemia. The guidelines list a range of treatment options.
“The management of MPNs has been variable in the past and largely driven by review articles and individual opinions,” said Ruben A. Mesa, MD, chair of the NCCN Guidelines Panel for MPN.
“The NCCN Guidelines Panel for MPN hopes these inaugural guidelines will help leverage the evidence base in MPN care for clear, well-informed treatment guidelines to hopefully improve quality of care and provide better outcomes for patients with MPN.”
Dr Mesa is scheduled to present the new NCCN guidelines during the NCCN 11th Annual Congress: Hematologic Malignancies™ on September 30, in a session titled, “Myeloprofilerative Neoplasms and Myelofibrosis: Evolving Management.” 
The National Comprehensive Cancer Network (NCCN) has published new clinical practice guidelines for myeloproliferative neoplasms (MPNs).
The current guidelines focus on the management of patients with myelofibrosis (MF), but NCCN said recommendations for managing essential thrombocythemia (ET) and polycythemia vera (PV) will be included in subsequent versions of the NCCN guidelines for MPNs.
The new guidelines provide recommendations on the workup and diagnosis of primary MF, post-ET MF, and post-PV MF.
The document also includes recommendations for managing MF-associated anemia, supportive care options, and treatment recommendations according to a patient’s risk group.
Treatment of low-risk MF
The guidelines recommend that patients with low-risk, asymptomatic MF be observed or enrolled in a clinical trial. They should be monitored for progression every 3 to 6 months.
Patients with low-risk, symptomatic MF should receive ruxolitinib or interferons or be enrolled on a clinical trial. They should be monitored for progression every 3 to 6 months.
If patients respond to treatment, they should continue to receive it. If they do not respond or lose their response, they should receive ruxolitinib or interferons or be enrolled on a clinical trial. If these patients progress, they should be treated according to their risk category.
Intermediate-1-risk MF
Patients with intermediate-1-risk MF should be assessed for symptom burden and observed if asymptomatic. If symptomatic, they should receive ruxolitinib, be enrolled on a clinical trial, or undergo allogeneic hematopoietic stem cell transplant (HSCT).
Patients should be monitored for response and progression every 3 to 6 months. If they respond to treatment, they should continue to receive it.
If patients do not respond or lose their response, they should be observed, receive ruxolitinib, be enrolled on a clinical trial, or undergo allogeneic HSCT. If these patients progress, they should be treated according to their risk category.
Intermediate-2- or high-risk MF
Patients who are transplant candidates should receive allogeneic HSCT.
Patients who are ineligible for transplant should be assessed for symptom burden. Those with a platelet count of 50,000 or lower should be considered for a clinical trial.
Those with higher platelet counts should receive ruxolitinib or be enrolled on a clinical trial. They should be monitored for response or progression every 3 to 6 months.
If these patients respond to treatment, they should continue on that treatment. If they do not respond or lose their response, the patients should be monitored for progression.
If they progress and are candidates for transplant, these patients should receive hypomethylating agents or chemotherapy to induce remission, followed by HSCT.
If the patients progress and are ineligible for transplant, they should be enrolled on a clinical trial or receive hypomethylating agents or chemotherapy.
For patients who are ineligible for transplant and only have symptomatic anemia, they should receive treatment to manage that anemia. The guidelines list a range of treatment options.
“The management of MPNs has been variable in the past and largely driven by review articles and individual opinions,” said Ruben A. Mesa, MD, chair of the NCCN Guidelines Panel for MPN.
“The NCCN Guidelines Panel for MPN hopes these inaugural guidelines will help leverage the evidence base in MPN care for clear, well-informed treatment guidelines to hopefully improve quality of care and provide better outcomes for patients with MPN.”
Dr Mesa is scheduled to present the new NCCN guidelines during the NCCN 11th Annual Congress: Hematologic Malignancies™ on September 30, in a session titled, “Myeloprofilerative Neoplasms and Myelofibrosis: Evolving Management.”
The National Comprehensive Cancer Network (NCCN) has published new clinical practice guidelines for myeloproliferative neoplasms (MPNs).
The current guidelines focus on the management of patients with myelofibrosis (MF), but NCCN said recommendations for managing essential thrombocythemia (ET) and polycythemia vera (PV) will be included in subsequent versions of the NCCN guidelines for MPNs.
The new guidelines provide recommendations on the workup and diagnosis of primary MF, post-ET MF, and post-PV MF.
The document also includes recommendations for managing MF-associated anemia, supportive care options, and treatment recommendations according to a patient’s risk group.
Treatment of low-risk MF
The guidelines recommend that patients with low-risk, asymptomatic MF be observed or enrolled in a clinical trial. They should be monitored for progression every 3 to 6 months.
Patients with low-risk, symptomatic MF should receive ruxolitinib or interferons or be enrolled on a clinical trial. They should be monitored for progression every 3 to 6 months.
If patients respond to treatment, they should continue to receive it. If they do not respond or lose their response, they should receive ruxolitinib or interferons or be enrolled on a clinical trial. If these patients progress, they should be treated according to their risk category.
Intermediate-1-risk MF
Patients with intermediate-1-risk MF should be assessed for symptom burden and observed if asymptomatic. If symptomatic, they should receive ruxolitinib, be enrolled on a clinical trial, or undergo allogeneic hematopoietic stem cell transplant (HSCT).
Patients should be monitored for response and progression every 3 to 6 months. If they respond to treatment, they should continue to receive it.
If patients do not respond or lose their response, they should be observed, receive ruxolitinib, be enrolled on a clinical trial, or undergo allogeneic HSCT. If these patients progress, they should be treated according to their risk category.
Intermediate-2- or high-risk MF
Patients who are transplant candidates should receive allogeneic HSCT.
Patients who are ineligible for transplant should be assessed for symptom burden. Those with a platelet count of 50,000 or lower should be considered for a clinical trial.
Those with higher platelet counts should receive ruxolitinib or be enrolled on a clinical trial. They should be monitored for response or progression every 3 to 6 months.
If these patients respond to treatment, they should continue on that treatment. If they do not respond or lose their response, the patients should be monitored for progression.
If they progress and are candidates for transplant, these patients should receive hypomethylating agents or chemotherapy to induce remission, followed by HSCT.
If the patients progress and are ineligible for transplant, they should be enrolled on a clinical trial or receive hypomethylating agents or chemotherapy.
For patients who are ineligible for transplant and only have symptomatic anemia, they should receive treatment to manage that anemia. The guidelines list a range of treatment options.
“The management of MPNs has been variable in the past and largely driven by review articles and individual opinions,” said Ruben A. Mesa, MD, chair of the NCCN Guidelines Panel for MPN.
“The NCCN Guidelines Panel for MPN hopes these inaugural guidelines will help leverage the evidence base in MPN care for clear, well-informed treatment guidelines to hopefully improve quality of care and provide better outcomes for patients with MPN.”
Dr Mesa is scheduled to present the new NCCN guidelines during the NCCN 11th Annual Congress: Hematologic Malignancies™ on September 30, in a session titled, “Myeloprofilerative Neoplasms and Myelofibrosis: Evolving Management.”
OSC calls for further review of allegations about Zika test
Photo by Graham Colm
The US Office of Special Counsel (OSC) has called for further review of allegations made about the Trioplex assay, a test used to detect Zika and other viruses.
A whistleblower recently alleged that the Centers for Disease Control and Prevention (CDC) has been using and promoting the Trioplex assay even though this test is nearly 40% less effective for Zika virus detection than another test, the Singleplex assay.
The CDC conducted an investigation that suggested this claim is not accurate, but the OSC has recommended additional review of the issue. (The OSC is an independent federal investigative and prosecutorial agency.)
Allegations
The allegations about the Trioplex assay were made by Robert Lanciotti, PhD, a CDC microbiologist based in Fort Collins, Colorado.
Dr Lanciotti conducted a study in which the Trioplex assay—which tests for Zika, dengue, and chikungunya—missed 39% of Zika infections detected by the Singleplex assay, which only tests for Zika.
Dr Lanciotti also raised concerns that the CDC’s Emergency Operations Center (EOC) withheld from public health laboratories information about the sensitivity differences between the Trioplex and Singleplex assays.
He said the CDC may have given laboratories the mistaken impression that Trioplex was a better test.
The Singleplex assay was made by Dr Lanciotti’s lab, while the Trioplex assay was developed at the CDC’s dengue branch lab in Puerto Rico.
Investigation
The OSC referred Dr Lanciotti’s claims to the Department of Health and Human Services (HHS) for investigation on July 1, 2016.
HHS Secretary Sylvia Mathews Burwell directed Steve Monroe, PhD, associate director for laboratory science and safety at the CDC, to conduct the investigation. The investigative team did not include employees who worked in EOC or in the zoonotic infectious diseases branch of the CDC.
The CDC said its investigation did not substantiate Dr Lanciotti’s claims. Investigators said they were unable to reach a “statistically valid conclusion about the relative performance” of the tests.
The CDC’s report pointed to a study conducted by its dengue branch in Puerto Rico that “found no difference in sensitivity” between the assays. The Trioplex assay was developed at this lab.
The report also said the CDC acted reasonably when it withheld information about the sensitivity differences between the Trioplex and Singleplex assays because there was conflicting data from different labs. The investigators said releasing that data could have created “considerable confusion during an ongoing emergency response.”
The CDC also noted that, in late August, the agency made changes intended to improve the sensitivity of the Trioplex assay, such as increasing sample volumes and allowing whole blood as a specimen type.
Response
Dr Lanciotti took issue with several points in the CDC’s report. Perhaps most importantly, he said “there was clearly enough data to warrant a ‘pause’ in the recommendation of the Trioplex until an extensive comparison could be performed.”
He referenced a multicenter study conducted independently by the Blood Systems Research Institute in San Francisco, California, which demonstrated the Trioplex assay’s lower sensitivity.
Dr Lanciotti added that the method used by this institution to assess the tests is “the most accurate method to evaluate the clinical sensitivity . . . of individual assays.”
Reassignment
Prior to disclosing his concerns to the OSC, Dr Lanciotti voiced the concerns internally and in an email to state public health officials in April 2016.
In May, he was reassigned to a non‐supervisory position within his lab. After the reassignment, Dr Lanciotti filed a whistleblower retaliation claim alleging that his diminished duties, from lab chief to a non‐supervisory position, was in reprisal for his disclosures.
After an investigation, the OSC secured an agreement from the CDC to reinstate Dr Lanciotti as chief of his lab.
OSC assessment
In a letter to President Barack Obama, Carolyn Lerner, head of the OSC, said the CDC “conducted a thorough investigation into Dr Lanciotti’s allegations, and its findings appear reasonable.”
On the other hand, Dr Lanciotti has raised “serious concerns” about the CDC’s findings.
“As the agency contemplates additional improvements or changes to the Zika testing protocol, I encourage CDC to review Dr Lanciotti’s comments, respond to each of his concerns, and utilize his expertise as the agency works to ensure it is implementing the most effective testing methods in response to this public health emergency,” Lerner said.
“I also encourage the CDC to promote scientific debate within its labs. Whistleblowers should be encouraged to speak out on matters of public concern.”
Photo by Graham Colm
The US Office of Special Counsel (OSC) has called for further review of allegations made about the Trioplex assay, a test used to detect Zika and other viruses.
A whistleblower recently alleged that the Centers for Disease Control and Prevention (CDC) has been using and promoting the Trioplex assay even though this test is nearly 40% less effective for Zika virus detection than another test, the Singleplex assay.
The CDC conducted an investigation that suggested this claim is not accurate, but the OSC has recommended additional review of the issue. (The OSC is an independent federal investigative and prosecutorial agency.)
Allegations
The allegations about the Trioplex assay were made by Robert Lanciotti, PhD, a CDC microbiologist based in Fort Collins, Colorado.
Dr Lanciotti conducted a study in which the Trioplex assay—which tests for Zika, dengue, and chikungunya—missed 39% of Zika infections detected by the Singleplex assay, which only tests for Zika.
Dr Lanciotti also raised concerns that the CDC’s Emergency Operations Center (EOC) withheld from public health laboratories information about the sensitivity differences between the Trioplex and Singleplex assays.
He said the CDC may have given laboratories the mistaken impression that Trioplex was a better test.
The Singleplex assay was made by Dr Lanciotti’s lab, while the Trioplex assay was developed at the CDC’s dengue branch lab in Puerto Rico.
Investigation
The OSC referred Dr Lanciotti’s claims to the Department of Health and Human Services (HHS) for investigation on July 1, 2016.
HHS Secretary Sylvia Mathews Burwell directed Steve Monroe, PhD, associate director for laboratory science and safety at the CDC, to conduct the investigation. The investigative team did not include employees who worked in EOC or in the zoonotic infectious diseases branch of the CDC.
The CDC said its investigation did not substantiate Dr Lanciotti’s claims. Investigators said they were unable to reach a “statistically valid conclusion about the relative performance” of the tests.
The CDC’s report pointed to a study conducted by its dengue branch in Puerto Rico that “found no difference in sensitivity” between the assays. The Trioplex assay was developed at this lab.
The report also said the CDC acted reasonably when it withheld information about the sensitivity differences between the Trioplex and Singleplex assays because there was conflicting data from different labs. The investigators said releasing that data could have created “considerable confusion during an ongoing emergency response.”
The CDC also noted that, in late August, the agency made changes intended to improve the sensitivity of the Trioplex assay, such as increasing sample volumes and allowing whole blood as a specimen type.
Response
Dr Lanciotti took issue with several points in the CDC’s report. Perhaps most importantly, he said “there was clearly enough data to warrant a ‘pause’ in the recommendation of the Trioplex until an extensive comparison could be performed.”
He referenced a multicenter study conducted independently by the Blood Systems Research Institute in San Francisco, California, which demonstrated the Trioplex assay’s lower sensitivity.
Dr Lanciotti added that the method used by this institution to assess the tests is “the most accurate method to evaluate the clinical sensitivity . . . of individual assays.”
Reassignment
Prior to disclosing his concerns to the OSC, Dr Lanciotti voiced the concerns internally and in an email to state public health officials in April 2016.
In May, he was reassigned to a non‐supervisory position within his lab. After the reassignment, Dr Lanciotti filed a whistleblower retaliation claim alleging that his diminished duties, from lab chief to a non‐supervisory position, was in reprisal for his disclosures.
After an investigation, the OSC secured an agreement from the CDC to reinstate Dr Lanciotti as chief of his lab.
OSC assessment
In a letter to President Barack Obama, Carolyn Lerner, head of the OSC, said the CDC “conducted a thorough investigation into Dr Lanciotti’s allegations, and its findings appear reasonable.”
On the other hand, Dr Lanciotti has raised “serious concerns” about the CDC’s findings.
“As the agency contemplates additional improvements or changes to the Zika testing protocol, I encourage CDC to review Dr Lanciotti’s comments, respond to each of his concerns, and utilize his expertise as the agency works to ensure it is implementing the most effective testing methods in response to this public health emergency,” Lerner said.
“I also encourage the CDC to promote scientific debate within its labs. Whistleblowers should be encouraged to speak out on matters of public concern.”
Photo by Graham Colm
The US Office of Special Counsel (OSC) has called for further review of allegations made about the Trioplex assay, a test used to detect Zika and other viruses.
A whistleblower recently alleged that the Centers for Disease Control and Prevention (CDC) has been using and promoting the Trioplex assay even though this test is nearly 40% less effective for Zika virus detection than another test, the Singleplex assay.
The CDC conducted an investigation that suggested this claim is not accurate, but the OSC has recommended additional review of the issue. (The OSC is an independent federal investigative and prosecutorial agency.)
Allegations
The allegations about the Trioplex assay were made by Robert Lanciotti, PhD, a CDC microbiologist based in Fort Collins, Colorado.
Dr Lanciotti conducted a study in which the Trioplex assay—which tests for Zika, dengue, and chikungunya—missed 39% of Zika infections detected by the Singleplex assay, which only tests for Zika.
Dr Lanciotti also raised concerns that the CDC’s Emergency Operations Center (EOC) withheld from public health laboratories information about the sensitivity differences between the Trioplex and Singleplex assays.
He said the CDC may have given laboratories the mistaken impression that Trioplex was a better test.
The Singleplex assay was made by Dr Lanciotti’s lab, while the Trioplex assay was developed at the CDC’s dengue branch lab in Puerto Rico.
Investigation
The OSC referred Dr Lanciotti’s claims to the Department of Health and Human Services (HHS) for investigation on July 1, 2016.
HHS Secretary Sylvia Mathews Burwell directed Steve Monroe, PhD, associate director for laboratory science and safety at the CDC, to conduct the investigation. The investigative team did not include employees who worked in EOC or in the zoonotic infectious diseases branch of the CDC.
The CDC said its investigation did not substantiate Dr Lanciotti’s claims. Investigators said they were unable to reach a “statistically valid conclusion about the relative performance” of the tests.
The CDC’s report pointed to a study conducted by its dengue branch in Puerto Rico that “found no difference in sensitivity” between the assays. The Trioplex assay was developed at this lab.
The report also said the CDC acted reasonably when it withheld information about the sensitivity differences between the Trioplex and Singleplex assays because there was conflicting data from different labs. The investigators said releasing that data could have created “considerable confusion during an ongoing emergency response.”
The CDC also noted that, in late August, the agency made changes intended to improve the sensitivity of the Trioplex assay, such as increasing sample volumes and allowing whole blood as a specimen type.
Response
Dr Lanciotti took issue with several points in the CDC’s report. Perhaps most importantly, he said “there was clearly enough data to warrant a ‘pause’ in the recommendation of the Trioplex until an extensive comparison could be performed.”
He referenced a multicenter study conducted independently by the Blood Systems Research Institute in San Francisco, California, which demonstrated the Trioplex assay’s lower sensitivity.
Dr Lanciotti added that the method used by this institution to assess the tests is “the most accurate method to evaluate the clinical sensitivity . . . of individual assays.”
Reassignment
Prior to disclosing his concerns to the OSC, Dr Lanciotti voiced the concerns internally and in an email to state public health officials in April 2016.
In May, he was reassigned to a non‐supervisory position within his lab. After the reassignment, Dr Lanciotti filed a whistleblower retaliation claim alleging that his diminished duties, from lab chief to a non‐supervisory position, was in reprisal for his disclosures.
After an investigation, the OSC secured an agreement from the CDC to reinstate Dr Lanciotti as chief of his lab.
OSC assessment
In a letter to President Barack Obama, Carolyn Lerner, head of the OSC, said the CDC “conducted a thorough investigation into Dr Lanciotti’s allegations, and its findings appear reasonable.”
On the other hand, Dr Lanciotti has raised “serious concerns” about the CDC’s findings.
“As the agency contemplates additional improvements or changes to the Zika testing protocol, I encourage CDC to review Dr Lanciotti’s comments, respond to each of his concerns, and utilize his expertise as the agency works to ensure it is implementing the most effective testing methods in response to this public health emergency,” Lerner said.
“I also encourage the CDC to promote scientific debate within its labs. Whistleblowers should be encouraged to speak out on matters of public concern.”
Database of research regulations gets update
for a clinical trial
Photo by Esther Dyson
The ClinRegs website has been updated and upgraded, according to the National Institute of Allergy and Infectious Diseases.
ClinRegs is an online database of country-specific information on clinical research regulations that was launched in 2014.
Now, the website houses regulatory information for 17 countries and has an interactive map on its homepage to provide a clearer picture of the countries included.
ClinRegs also has a hyperlinked table of contents on each country page that is intended to provide easier navigation.
Drop-down menus allow users to switch between country profiles and make comparisons between countries.
In addition, ClinRegs now provides a Quick Facts table with discrete pieces of information for each country.
And a feedback link has been added to the site to make it easy for users to submit comments or updates to regulations.
for a clinical trial
Photo by Esther Dyson
The ClinRegs website has been updated and upgraded, according to the National Institute of Allergy and Infectious Diseases.
ClinRegs is an online database of country-specific information on clinical research regulations that was launched in 2014.
Now, the website houses regulatory information for 17 countries and has an interactive map on its homepage to provide a clearer picture of the countries included.
ClinRegs also has a hyperlinked table of contents on each country page that is intended to provide easier navigation.
Drop-down menus allow users to switch between country profiles and make comparisons between countries.
In addition, ClinRegs now provides a Quick Facts table with discrete pieces of information for each country.
And a feedback link has been added to the site to make it easy for users to submit comments or updates to regulations.
for a clinical trial
Photo by Esther Dyson
The ClinRegs website has been updated and upgraded, according to the National Institute of Allergy and Infectious Diseases.
ClinRegs is an online database of country-specific information on clinical research regulations that was launched in 2014.
Now, the website houses regulatory information for 17 countries and has an interactive map on its homepage to provide a clearer picture of the countries included.
ClinRegs also has a hyperlinked table of contents on each country page that is intended to provide easier navigation.
Drop-down menus allow users to switch between country profiles and make comparisons between countries.
In addition, ClinRegs now provides a Quick Facts table with discrete pieces of information for each country.
And a feedback link has been added to the site to make it easy for users to submit comments or updates to regulations.
Combo disappoints in newly diagnosed MM
Top-line results from the phase 3 CLARION trial suggest that treatment with carfilzomib, melphalan, and prednisone (KMP) is not superior to treatment with bortezomib, melphalan, and prednisone (VMP).
The trial was designed to compare KMP and VMP in patients with newly diagnosed multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplant.
The results showed that progression-free survival (PFS) rates were similar with the 2 regimens.
And although overall survival data are not yet mature, there seems to be a trend favoring the VMP regimen.
Amgen, the company developing carfilzomib, released these results yesterday.
“The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we’ve seen in the second-line setting,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen.
“However, the myeloma landscape has changed dramatically since the design of the CLARION study, with very few newly diagnosed patients treated with
melphalan-based regimens, particularly in the US. We remain committed to exploring Kyprolis in combination with other agents to advance the treatment of multiple myeloma.”
Dr Harper said he could not comment on whether the CLARION trial will continue, as Amgen hopes to present data from the trial at the 2016 ASH Annual Meeting.
The CLARION trial is a head-to-head, randomized study in transplant-ineligible patients with newly diagnosed MM. A total of 955 patients were randomized 1:1 to receive KMP or VMP for 54 weeks. The median patient age was 72.
The trial did not meet the primary endpoint of superiority in PFS. The median PFS was 22.3 months in the KMP arm and 22.1 months in the VMP arm. The hazard ratio was 0.91 (95% CI, 0.75-1.10), and the difference between the arms was not statistically significant.
The data for overall survival, a secondary endpoint, are not yet mature. But the observed hazard ratio was 1.21 (95% CI, 0.90-1.64), and there was no significant difference between the treatment arms.
The incidence of grade 3 or higher adverse events was 74.7% in the KMP arm and 76.2% in the VMP arm.
The incidence of grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5% in the KMP arm and 35.1% in the VMP arm.
Fatal treatment-emergent adverse events occurred in 6.5% of patients in the KMP arm and 4.3% of those in the VMP arm.
Top-line results from the phase 3 CLARION trial suggest that treatment with carfilzomib, melphalan, and prednisone (KMP) is not superior to treatment with bortezomib, melphalan, and prednisone (VMP).
The trial was designed to compare KMP and VMP in patients with newly diagnosed multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplant.
The results showed that progression-free survival (PFS) rates were similar with the 2 regimens.
And although overall survival data are not yet mature, there seems to be a trend favoring the VMP regimen.
Amgen, the company developing carfilzomib, released these results yesterday.
“The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we’ve seen in the second-line setting,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen.
“However, the myeloma landscape has changed dramatically since the design of the CLARION study, with very few newly diagnosed patients treated with
melphalan-based regimens, particularly in the US. We remain committed to exploring Kyprolis in combination with other agents to advance the treatment of multiple myeloma.”
Dr Harper said he could not comment on whether the CLARION trial will continue, as Amgen hopes to present data from the trial at the 2016 ASH Annual Meeting.
The CLARION trial is a head-to-head, randomized study in transplant-ineligible patients with newly diagnosed MM. A total of 955 patients were randomized 1:1 to receive KMP or VMP for 54 weeks. The median patient age was 72.
The trial did not meet the primary endpoint of superiority in PFS. The median PFS was 22.3 months in the KMP arm and 22.1 months in the VMP arm. The hazard ratio was 0.91 (95% CI, 0.75-1.10), and the difference between the arms was not statistically significant.
The data for overall survival, a secondary endpoint, are not yet mature. But the observed hazard ratio was 1.21 (95% CI, 0.90-1.64), and there was no significant difference between the treatment arms.
The incidence of grade 3 or higher adverse events was 74.7% in the KMP arm and 76.2% in the VMP arm.
The incidence of grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5% in the KMP arm and 35.1% in the VMP arm.
Fatal treatment-emergent adverse events occurred in 6.5% of patients in the KMP arm and 4.3% of those in the VMP arm.
Top-line results from the phase 3 CLARION trial suggest that treatment with carfilzomib, melphalan, and prednisone (KMP) is not superior to treatment with bortezomib, melphalan, and prednisone (VMP).
The trial was designed to compare KMP and VMP in patients with newly diagnosed multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplant.
The results showed that progression-free survival (PFS) rates were similar with the 2 regimens.
And although overall survival data are not yet mature, there seems to be a trend favoring the VMP regimen.
Amgen, the company developing carfilzomib, released these results yesterday.
“The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we’ve seen in the second-line setting,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen.
“However, the myeloma landscape has changed dramatically since the design of the CLARION study, with very few newly diagnosed patients treated with
melphalan-based regimens, particularly in the US. We remain committed to exploring Kyprolis in combination with other agents to advance the treatment of multiple myeloma.”
Dr Harper said he could not comment on whether the CLARION trial will continue, as Amgen hopes to present data from the trial at the 2016 ASH Annual Meeting.
The CLARION trial is a head-to-head, randomized study in transplant-ineligible patients with newly diagnosed MM. A total of 955 patients were randomized 1:1 to receive KMP or VMP for 54 weeks. The median patient age was 72.
The trial did not meet the primary endpoint of superiority in PFS. The median PFS was 22.3 months in the KMP arm and 22.1 months in the VMP arm. The hazard ratio was 0.91 (95% CI, 0.75-1.10), and the difference between the arms was not statistically significant.
The data for overall survival, a secondary endpoint, are not yet mature. But the observed hazard ratio was 1.21 (95% CI, 0.90-1.64), and there was no significant difference between the treatment arms.
The incidence of grade 3 or higher adverse events was 74.7% in the KMP arm and 76.2% in the VMP arm.
The incidence of grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5% in the KMP arm and 35.1% in the VMP arm.
Fatal treatment-emergent adverse events occurred in 6.5% of patients in the KMP arm and 4.3% of those in the VMP arm.
KTE-C19 produces responses in aggressive NHL
Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).
KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of
79% and a complete response (CR) rate of 52%.
However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.
Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.
ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).
Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).
The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 106 CAR T cells/kg).
Responses
In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.
In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.
Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.
Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.
Longer follow-up data are not yet available for the phase 2 portion of the study.
Safety
For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).
Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.
Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.
Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.
ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.
Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).
KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of
79% and a complete response (CR) rate of 52%.
However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.
Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.
ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).
Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).
The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 106 CAR T cells/kg).
Responses
In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.
In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.
Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.
Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.
Longer follow-up data are not yet available for the phase 2 portion of the study.
Safety
For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).
Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.
Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.
Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.
ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.
Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).
KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of
79% and a complete response (CR) rate of 52%.
However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.
Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.
ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).
Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).
The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 106 CAR T cells/kg).
Responses
In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.
In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.
Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.
Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.
Longer follow-up data are not yet available for the phase 2 portion of the study.
Safety
For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).
Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.
Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.
Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.
ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.
Therapy granted orphan designation to prevent GVHD
Image from PLOS ONE
The US Food and Drug Administration (FDA) has granted orphan drug designation to a programmed cellular immunotherapy known as ProTmune™.
The designation is for ProTmune to be used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).
This indication covers a range of diseases, including hematologic malignancies and genetic disorders.
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About ProTmune
ProTmune is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with 2 small molecules—FT1050 and FT4145—to enhance the biological properties and therapeutic function of the graft’s immune cells.
The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
ProTmune is being developed by Fate Therapeutics, Inc.
The company is conducting a phase 1/2 trial testing ProTmune for the prevention of acute GVHD and cytomegalovirus infection in adults with hematologic malignancies who are undergoing allogeneic HSCT.
ProTmune was previously granted fast track designation from the FDA.
“The granting of both orphan drug and fast track designations for ProTmune validates the product candidate’s unique therapeutic potential to address life-threatening complications and improve the curative potential of allogeneic [HSCT],” said Scott Wolchko, president and chief executive officer of Fate Therapeutics.
“Graft-versus-host disease is a significant cause of morbidity and mortality in patients undergoing allogeneic [HSCT], and there are no FDA-approved therapies to prevent its occurrence. Through our development of ProTmune, we seek to transform the allogeneic [HSCT] paradigm by providing immunocompromised patients a therapeutically optimized donor graft containing immune cells with reduced alloreactivity and enhanced infection-fighting and anti-tumor properties.”
Image from PLOS ONE
The US Food and Drug Administration (FDA) has granted orphan drug designation to a programmed cellular immunotherapy known as ProTmune™.
The designation is for ProTmune to be used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).
This indication covers a range of diseases, including hematologic malignancies and genetic disorders.
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About ProTmune
ProTmune is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with 2 small molecules—FT1050 and FT4145—to enhance the biological properties and therapeutic function of the graft’s immune cells.
The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
ProTmune is being developed by Fate Therapeutics, Inc.
The company is conducting a phase 1/2 trial testing ProTmune for the prevention of acute GVHD and cytomegalovirus infection in adults with hematologic malignancies who are undergoing allogeneic HSCT.
ProTmune was previously granted fast track designation from the FDA.
“The granting of both orphan drug and fast track designations for ProTmune validates the product candidate’s unique therapeutic potential to address life-threatening complications and improve the curative potential of allogeneic [HSCT],” said Scott Wolchko, president and chief executive officer of Fate Therapeutics.
“Graft-versus-host disease is a significant cause of morbidity and mortality in patients undergoing allogeneic [HSCT], and there are no FDA-approved therapies to prevent its occurrence. Through our development of ProTmune, we seek to transform the allogeneic [HSCT] paradigm by providing immunocompromised patients a therapeutically optimized donor graft containing immune cells with reduced alloreactivity and enhanced infection-fighting and anti-tumor properties.”
Image from PLOS ONE
The US Food and Drug Administration (FDA) has granted orphan drug designation to a programmed cellular immunotherapy known as ProTmune™.
The designation is for ProTmune to be used as graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).
This indication covers a range of diseases, including hematologic malignancies and genetic disorders.
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About ProTmune
ProTmune is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with 2 small molecules—FT1050 and FT4145—to enhance the biological properties and therapeutic function of the graft’s immune cells.
The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
ProTmune is being developed by Fate Therapeutics, Inc.
The company is conducting a phase 1/2 trial testing ProTmune for the prevention of acute GVHD and cytomegalovirus infection in adults with hematologic malignancies who are undergoing allogeneic HSCT.
ProTmune was previously granted fast track designation from the FDA.
“The granting of both orphan drug and fast track designations for ProTmune validates the product candidate’s unique therapeutic potential to address life-threatening complications and improve the curative potential of allogeneic [HSCT],” said Scott Wolchko, president and chief executive officer of Fate Therapeutics.
“Graft-versus-host disease is a significant cause of morbidity and mortality in patients undergoing allogeneic [HSCT], and there are no FDA-approved therapies to prevent its occurrence. Through our development of ProTmune, we seek to transform the allogeneic [HSCT] paradigm by providing immunocompromised patients a therapeutically optimized donor graft containing immune cells with reduced alloreactivity and enhanced infection-fighting and anti-tumor properties.”
Cells might protect cancer patients from infection
receiving chemotherapy
Photo by Rhoda Baer
Researchers say they have discovered a type of macrophage that may protect against lung infections during chemotherapy.
These macrophages, found in the lungs of mice, were able to survive chemotherapy.
The macrophages could remove bacteria when activated by a vaccine, which improved survival in mice with lethal bacterial pneumonia that had received chemotherapy and were therefore depleted of neutrophils.
The researchers said these results suggest the cells—known as vaccine-induced macrophages (ViMs)— might be able to protect cancer patients from life-threatening infections.
“We have identified a new form of housekeeping macrophage in mice that may, in future, be harnessed to protect against lung infections—like bacterial pneumonia—that remain one of the greatest threats to survival of cancer patients during chemotherapy,” said Peter Murray, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Murray and his colleagues detailed this discovery in PNAS.
Working in a mouse model that mimics infection in chemotherapy-treated patients, the researchers found that vaccination protected mice from Pseudomonas aeruginosa pneumonia.
The quest to understand how such protection was possible in the absence of neutrophils led the team to discover ViMs.
The researchers found that ViMs were produced in the lungs following vaccination, proliferated locally, and could persist for at least a month.
Analyses suggested ViMs are closely related to alveolar macrophages, which originate in the embryo, reside in the air-exposed surfaces of alveoli, and are self-maintained in adults.
“All lines of cellular and molecular evidence in this study point to alveolar macrophages as the source of ViMs,” Dr Murray said.
However, unlike alveolar macrophages, the population of ViMs remained stable during chemotherapy and exhibited enhanced phagocytic activity.
When ViMs were transferred to unvaccinated mice depleted of neutrophils via chemotherapy, the animals were protected from lethal Pseudomonas infections.
“We now know that increasing the number of ViMs in the tissue can compensate for the immune deficit caused by chemotherapy,” said study author Akinobu Kamei, MD, of St. Jude Children’s Research Hospital.
“In this study, we relied on vaccination prior to chemotherapy. Going forward, we will explore other, more practical methods for use at the bedside to effectively induce tissue-resident macrophages like ViMs.”
The possible approaches include using drugs or cytokines to induce protection in the immune-compromised host.
receiving chemotherapy
Photo by Rhoda Baer
Researchers say they have discovered a type of macrophage that may protect against lung infections during chemotherapy.
These macrophages, found in the lungs of mice, were able to survive chemotherapy.
The macrophages could remove bacteria when activated by a vaccine, which improved survival in mice with lethal bacterial pneumonia that had received chemotherapy and were therefore depleted of neutrophils.
The researchers said these results suggest the cells—known as vaccine-induced macrophages (ViMs)— might be able to protect cancer patients from life-threatening infections.
“We have identified a new form of housekeeping macrophage in mice that may, in future, be harnessed to protect against lung infections—like bacterial pneumonia—that remain one of the greatest threats to survival of cancer patients during chemotherapy,” said Peter Murray, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Murray and his colleagues detailed this discovery in PNAS.
Working in a mouse model that mimics infection in chemotherapy-treated patients, the researchers found that vaccination protected mice from Pseudomonas aeruginosa pneumonia.
The quest to understand how such protection was possible in the absence of neutrophils led the team to discover ViMs.
The researchers found that ViMs were produced in the lungs following vaccination, proliferated locally, and could persist for at least a month.
Analyses suggested ViMs are closely related to alveolar macrophages, which originate in the embryo, reside in the air-exposed surfaces of alveoli, and are self-maintained in adults.
“All lines of cellular and molecular evidence in this study point to alveolar macrophages as the source of ViMs,” Dr Murray said.
However, unlike alveolar macrophages, the population of ViMs remained stable during chemotherapy and exhibited enhanced phagocytic activity.
When ViMs were transferred to unvaccinated mice depleted of neutrophils via chemotherapy, the animals were protected from lethal Pseudomonas infections.
“We now know that increasing the number of ViMs in the tissue can compensate for the immune deficit caused by chemotherapy,” said study author Akinobu Kamei, MD, of St. Jude Children’s Research Hospital.
“In this study, we relied on vaccination prior to chemotherapy. Going forward, we will explore other, more practical methods for use at the bedside to effectively induce tissue-resident macrophages like ViMs.”
The possible approaches include using drugs or cytokines to induce protection in the immune-compromised host.
receiving chemotherapy
Photo by Rhoda Baer
Researchers say they have discovered a type of macrophage that may protect against lung infections during chemotherapy.
These macrophages, found in the lungs of mice, were able to survive chemotherapy.
The macrophages could remove bacteria when activated by a vaccine, which improved survival in mice with lethal bacterial pneumonia that had received chemotherapy and were therefore depleted of neutrophils.
The researchers said these results suggest the cells—known as vaccine-induced macrophages (ViMs)— might be able to protect cancer patients from life-threatening infections.
“We have identified a new form of housekeeping macrophage in mice that may, in future, be harnessed to protect against lung infections—like bacterial pneumonia—that remain one of the greatest threats to survival of cancer patients during chemotherapy,” said Peter Murray, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Murray and his colleagues detailed this discovery in PNAS.
Working in a mouse model that mimics infection in chemotherapy-treated patients, the researchers found that vaccination protected mice from Pseudomonas aeruginosa pneumonia.
The quest to understand how such protection was possible in the absence of neutrophils led the team to discover ViMs.
The researchers found that ViMs were produced in the lungs following vaccination, proliferated locally, and could persist for at least a month.
Analyses suggested ViMs are closely related to alveolar macrophages, which originate in the embryo, reside in the air-exposed surfaces of alveoli, and are self-maintained in adults.
“All lines of cellular and molecular evidence in this study point to alveolar macrophages as the source of ViMs,” Dr Murray said.
However, unlike alveolar macrophages, the population of ViMs remained stable during chemotherapy and exhibited enhanced phagocytic activity.
When ViMs were transferred to unvaccinated mice depleted of neutrophils via chemotherapy, the animals were protected from lethal Pseudomonas infections.
“We now know that increasing the number of ViMs in the tissue can compensate for the immune deficit caused by chemotherapy,” said study author Akinobu Kamei, MD, of St. Jude Children’s Research Hospital.
“In this study, we relied on vaccination prior to chemotherapy. Going forward, we will explore other, more practical methods for use at the bedside to effectively induce tissue-resident macrophages like ViMs.”
The possible approaches include using drugs or cytokines to induce protection in the immune-compromised host.
Preserved slides provide insight into European malaria
Photo from the Institute
of Evolutionary Biology
A new study published in PNAS has provided insights regarding the origin and spread of European malaria.
The malaria-causing parasites Plasmodium vivax and Plasmodium falciparum were eradicated in Europe in the mid-twentieth century.
Now, researchers have recovered genetic data from European samples of malaria preserved on microscope slides in the 1940s.
The team performed second-generation sequencing on DNA extracted from 3 of the slides, which generated millions of sequences of malaria-causing parasites.
The researchers were then able to reconstruct the parasites’ mitochondrial genomes and compare them with those of present-day samples worldwide.
“The European sequence of P vivax is closely related to the most common strain currently found in Central and South America,” said study author Carles Lalueza-Fox, PhD, of the Institute of Evolutionary Biology (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra) in Barcelona, Spain.
“This suggests that the pathogen was introduced to the Americas by European colonists after Columbus. In contrast, the European sequence of P falciparum belongs to a strain which has only been found in India. This indicates that the pathogen of the most severe form of malaria was introduced to Europe from the Indian subcontinent, probably some 2500 years ago.”
The European samples the researchers analyzed were dated between 1942 and 1944. They originate from an old antimalarial center inaugurated in 1925 in Sant Jaume d’Enveja, on the Ebro Delta, located in Spain’s north-eastern region of Tarragona.
The center’s head, Ildefonso Canicio, spent decades treating malaria sufferers who worked in the area’s rice fields and ultimately contracted the disease himself.
Following Dr Canicio’s death in 1961, some of his slides, which were used for diagnostic purposes, were saved from destruction when they were recognized by his descendants, who allowed them to be used in the current study.
“It is still possible to see malaria-carrying parasites on the slides when they are studied under the microscope,” Dr Lalueza-Fox said. “However, the quantity of the pathogen’s DNA available in a single drop of blood is very limited, and when you add to that the issue of poor preservation after 70 years, it is clear why this type of study has never been carried out.”
Still, the researchers said this study has shown that historic specimens can be an important source of insight into the genetics of extinct or eradicated pathogens.
“Analyzing the nuclear genome in these pathogens will allow us to know more about the mutations which have made current-day strains resistant to different drugs, given that the European Plasmodium which has been retrieved is older than all of these treatments,” said study author Pere Gelabert, also of the Institute of Evolutionary Biology.
Photo from the Institute
of Evolutionary Biology
A new study published in PNAS has provided insights regarding the origin and spread of European malaria.
The malaria-causing parasites Plasmodium vivax and Plasmodium falciparum were eradicated in Europe in the mid-twentieth century.
Now, researchers have recovered genetic data from European samples of malaria preserved on microscope slides in the 1940s.
The team performed second-generation sequencing on DNA extracted from 3 of the slides, which generated millions of sequences of malaria-causing parasites.
The researchers were then able to reconstruct the parasites’ mitochondrial genomes and compare them with those of present-day samples worldwide.
“The European sequence of P vivax is closely related to the most common strain currently found in Central and South America,” said study author Carles Lalueza-Fox, PhD, of the Institute of Evolutionary Biology (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra) in Barcelona, Spain.
“This suggests that the pathogen was introduced to the Americas by European colonists after Columbus. In contrast, the European sequence of P falciparum belongs to a strain which has only been found in India. This indicates that the pathogen of the most severe form of malaria was introduced to Europe from the Indian subcontinent, probably some 2500 years ago.”
The European samples the researchers analyzed were dated between 1942 and 1944. They originate from an old antimalarial center inaugurated in 1925 in Sant Jaume d’Enveja, on the Ebro Delta, located in Spain’s north-eastern region of Tarragona.
The center’s head, Ildefonso Canicio, spent decades treating malaria sufferers who worked in the area’s rice fields and ultimately contracted the disease himself.
Following Dr Canicio’s death in 1961, some of his slides, which were used for diagnostic purposes, were saved from destruction when they were recognized by his descendants, who allowed them to be used in the current study.
“It is still possible to see malaria-carrying parasites on the slides when they are studied under the microscope,” Dr Lalueza-Fox said. “However, the quantity of the pathogen’s DNA available in a single drop of blood is very limited, and when you add to that the issue of poor preservation after 70 years, it is clear why this type of study has never been carried out.”
Still, the researchers said this study has shown that historic specimens can be an important source of insight into the genetics of extinct or eradicated pathogens.
“Analyzing the nuclear genome in these pathogens will allow us to know more about the mutations which have made current-day strains resistant to different drugs, given that the European Plasmodium which has been retrieved is older than all of these treatments,” said study author Pere Gelabert, also of the Institute of Evolutionary Biology.
Photo from the Institute
of Evolutionary Biology
A new study published in PNAS has provided insights regarding the origin and spread of European malaria.
The malaria-causing parasites Plasmodium vivax and Plasmodium falciparum were eradicated in Europe in the mid-twentieth century.
Now, researchers have recovered genetic data from European samples of malaria preserved on microscope slides in the 1940s.
The team performed second-generation sequencing on DNA extracted from 3 of the slides, which generated millions of sequences of malaria-causing parasites.
The researchers were then able to reconstruct the parasites’ mitochondrial genomes and compare them with those of present-day samples worldwide.
“The European sequence of P vivax is closely related to the most common strain currently found in Central and South America,” said study author Carles Lalueza-Fox, PhD, of the Institute of Evolutionary Biology (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra) in Barcelona, Spain.
“This suggests that the pathogen was introduced to the Americas by European colonists after Columbus. In contrast, the European sequence of P falciparum belongs to a strain which has only been found in India. This indicates that the pathogen of the most severe form of malaria was introduced to Europe from the Indian subcontinent, probably some 2500 years ago.”
The European samples the researchers analyzed were dated between 1942 and 1944. They originate from an old antimalarial center inaugurated in 1925 in Sant Jaume d’Enveja, on the Ebro Delta, located in Spain’s north-eastern region of Tarragona.
The center’s head, Ildefonso Canicio, spent decades treating malaria sufferers who worked in the area’s rice fields and ultimately contracted the disease himself.
Following Dr Canicio’s death in 1961, some of his slides, which were used for diagnostic purposes, were saved from destruction when they were recognized by his descendants, who allowed them to be used in the current study.
“It is still possible to see malaria-carrying parasites on the slides when they are studied under the microscope,” Dr Lalueza-Fox said. “However, the quantity of the pathogen’s DNA available in a single drop of blood is very limited, and when you add to that the issue of poor preservation after 70 years, it is clear why this type of study has never been carried out.”
Still, the researchers said this study has shown that historic specimens can be an important source of insight into the genetics of extinct or eradicated pathogens.
“Analyzing the nuclear genome in these pathogens will allow us to know more about the mutations which have made current-day strains resistant to different drugs, given that the European Plasmodium which has been retrieved is older than all of these treatments,” said study author Pere Gelabert, also of the Institute of Evolutionary Biology.
EMA and FDA collaborate to combat rare diseases
Photo courtesy of the FDA
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have set up a new working group, or “cluster,” on rare diseases.
This means the EMA and FDA will hold regular meetings via teleconference to share information on the regulation of medicines for rare diseases.
The cluster will provide a forum for the confidential exchange of draft documents, proposed policies, and detailed information supporting the scientific basis for decision-making on medicine development.
The agencies will exchange information on topics such as:
- The design of clinical trials in small populations and the use of statistical analysis methods
- The selection and validation of trial endpoints
- Preclinical evidence to support development programs
- The design of post-marketing studies—in particular, in the context of early access mechanisms such as the EMA’s conditional marketing authorization and the FDA’s accelerated approval
- Risk management strategies for long-term safety issues with medicines for rare diseases.
The first meeting of the rare diseases cluster took place on September 23, 2016. The cluster will initially meet once a month via teleconference and will be chaired jointly by the FDA and EMA.
The creation of this cluster is the latest step in the EMA’s and FDA’s wider objective to expand and reinforce international collaboration.
The clusters established by the agencies focus on areas where the parties involved could benefit from an intensified exchange of information and strengthened collaboration.
The existing EMA/FDA clusters address issues related to patient engagement, biosimilars, orphan medicines, cancer drugs, medicines for children, and pharmacovigilance, among other topics.
Photo courtesy of the FDA
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have set up a new working group, or “cluster,” on rare diseases.
This means the EMA and FDA will hold regular meetings via teleconference to share information on the regulation of medicines for rare diseases.
The cluster will provide a forum for the confidential exchange of draft documents, proposed policies, and detailed information supporting the scientific basis for decision-making on medicine development.
The agencies will exchange information on topics such as:
- The design of clinical trials in small populations and the use of statistical analysis methods
- The selection and validation of trial endpoints
- Preclinical evidence to support development programs
- The design of post-marketing studies—in particular, in the context of early access mechanisms such as the EMA’s conditional marketing authorization and the FDA’s accelerated approval
- Risk management strategies for long-term safety issues with medicines for rare diseases.
The first meeting of the rare diseases cluster took place on September 23, 2016. The cluster will initially meet once a month via teleconference and will be chaired jointly by the FDA and EMA.
The creation of this cluster is the latest step in the EMA’s and FDA’s wider objective to expand and reinforce international collaboration.
The clusters established by the agencies focus on areas where the parties involved could benefit from an intensified exchange of information and strengthened collaboration.
The existing EMA/FDA clusters address issues related to patient engagement, biosimilars, orphan medicines, cancer drugs, medicines for children, and pharmacovigilance, among other topics.
Photo courtesy of the FDA
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have set up a new working group, or “cluster,” on rare diseases.
This means the EMA and FDA will hold regular meetings via teleconference to share information on the regulation of medicines for rare diseases.
The cluster will provide a forum for the confidential exchange of draft documents, proposed policies, and detailed information supporting the scientific basis for decision-making on medicine development.
The agencies will exchange information on topics such as:
- The design of clinical trials in small populations and the use of statistical analysis methods
- The selection and validation of trial endpoints
- Preclinical evidence to support development programs
- The design of post-marketing studies—in particular, in the context of early access mechanisms such as the EMA’s conditional marketing authorization and the FDA’s accelerated approval
- Risk management strategies for long-term safety issues with medicines for rare diseases.
The first meeting of the rare diseases cluster took place on September 23, 2016. The cluster will initially meet once a month via teleconference and will be chaired jointly by the FDA and EMA.
The creation of this cluster is the latest step in the EMA’s and FDA’s wider objective to expand and reinforce international collaboration.
The clusters established by the agencies focus on areas where the parties involved could benefit from an intensified exchange of information and strengthened collaboration.
The existing EMA/FDA clusters address issues related to patient engagement, biosimilars, orphan medicines, cancer drugs, medicines for children, and pharmacovigilance, among other topics.
How anti-CD44 antibodies fight AML
Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML.
Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML.
Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML.