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Study suggests tests overused in monoclonal gammopathies
Photo by Phil Jones
A series of tests used to diagnose and monitor monoclonal gammopathies may fail to benefit patients while increasing healthcare costs, according to research published in The American Journal of Clinical Pathology.
Researchers conducted a review of all tests for investigating monoclonal gammopathies at a single institution and found that fewer than half of the serum immunofixation and serum free light chain assays performed were actually warranted.
According to the researchers, these results suggest that, instead of ordering individual tests, physicians should request an initial workup for monoclonal gammopathy.
Once pathologists interpret results of a screening serum protein electrophoresis (SPEP) and examine the patient’s medical record, they can decide what, if any, additional tests are needed.
“These are stepwise things,” said study author Gurmukh Singh, MD, PhD, of the Medical College of Georgia at Augusta University.
“If it’s a new patient, do this. If it’s a known patient, do that. Results drive it. That will reduce the number of tests that are done without in any way being of detriment to the patient or the quality of care.”
To conduct this study, Dr Singh and his colleagues reviewed the history of 237 patients, ages 19 to 87, who had a total of 1503 episodes of testing.
In addition to SPEP, many patients had serum immunofixation electrophoresis and/or serum free light chain assays.
But the researchers found that only 46% of the serum immunofixation and 42% of the serum free light chain assays were warranted.
The 2 tests were ordered multiple times in patients in whom M-protein was easily detected with SPEP. In fact, for most patients with measurable levels of M-protein, SPEP can be used to follow the course of the disease and treatment, the researchers said.
“About 40% to 50% of the second tests are not needed or adding value,” Dr Sing stressed.
In fact, he and his colleagues estimated that putting an end to unnecessary testing would have saved $64,182.95 per year in healthcare costs at this institution.
Therefore, the researchers propose using an algorithm that would put more of the decision-making in the hands of pathologists interpreting the tests.
An example of when serum immunofixation and serum free light chain assays should be done at least once is in a new patient when M-protein is first found, Dr Singh said. The additional tests might also be beneficial for patients under treatment for multiple myeloma, to ensure there are no trace amounts left of the abnormal protein.
Dr Singh added that testing patterns similar to those observed in this study are in play in hospitals across the US. However, a protocol similar to the one he is proposing has safely enabled up to a 60% reduction in the volume of second tests at a Missouri hospital where it has been in use for about 8 years.
“It’s better for patients and for healthcare delivery in general,” Dr Singh said. “Why spend money that you don’t need to spend when you are not gaining information that will benefit the patient’s outcome?” 
Photo by Phil Jones
A series of tests used to diagnose and monitor monoclonal gammopathies may fail to benefit patients while increasing healthcare costs, according to research published in The American Journal of Clinical Pathology.
Researchers conducted a review of all tests for investigating monoclonal gammopathies at a single institution and found that fewer than half of the serum immunofixation and serum free light chain assays performed were actually warranted.
According to the researchers, these results suggest that, instead of ordering individual tests, physicians should request an initial workup for monoclonal gammopathy.
Once pathologists interpret results of a screening serum protein electrophoresis (SPEP) and examine the patient’s medical record, they can decide what, if any, additional tests are needed.
“These are stepwise things,” said study author Gurmukh Singh, MD, PhD, of the Medical College of Georgia at Augusta University.
“If it’s a new patient, do this. If it’s a known patient, do that. Results drive it. That will reduce the number of tests that are done without in any way being of detriment to the patient or the quality of care.”
To conduct this study, Dr Singh and his colleagues reviewed the history of 237 patients, ages 19 to 87, who had a total of 1503 episodes of testing.
In addition to SPEP, many patients had serum immunofixation electrophoresis and/or serum free light chain assays.
But the researchers found that only 46% of the serum immunofixation and 42% of the serum free light chain assays were warranted.
The 2 tests were ordered multiple times in patients in whom M-protein was easily detected with SPEP. In fact, for most patients with measurable levels of M-protein, SPEP can be used to follow the course of the disease and treatment, the researchers said.
“About 40% to 50% of the second tests are not needed or adding value,” Dr Sing stressed.
In fact, he and his colleagues estimated that putting an end to unnecessary testing would have saved $64,182.95 per year in healthcare costs at this institution.
Therefore, the researchers propose using an algorithm that would put more of the decision-making in the hands of pathologists interpreting the tests.
An example of when serum immunofixation and serum free light chain assays should be done at least once is in a new patient when M-protein is first found, Dr Singh said. The additional tests might also be beneficial for patients under treatment for multiple myeloma, to ensure there are no trace amounts left of the abnormal protein.
Dr Singh added that testing patterns similar to those observed in this study are in play in hospitals across the US. However, a protocol similar to the one he is proposing has safely enabled up to a 60% reduction in the volume of second tests at a Missouri hospital where it has been in use for about 8 years.
“It’s better for patients and for healthcare delivery in general,” Dr Singh said. “Why spend money that you don’t need to spend when you are not gaining information that will benefit the patient’s outcome?”
Photo by Phil Jones
A series of tests used to diagnose and monitor monoclonal gammopathies may fail to benefit patients while increasing healthcare costs, according to research published in The American Journal of Clinical Pathology.
Researchers conducted a review of all tests for investigating monoclonal gammopathies at a single institution and found that fewer than half of the serum immunofixation and serum free light chain assays performed were actually warranted.
According to the researchers, these results suggest that, instead of ordering individual tests, physicians should request an initial workup for monoclonal gammopathy.
Once pathologists interpret results of a screening serum protein electrophoresis (SPEP) and examine the patient’s medical record, they can decide what, if any, additional tests are needed.
“These are stepwise things,” said study author Gurmukh Singh, MD, PhD, of the Medical College of Georgia at Augusta University.
“If it’s a new patient, do this. If it’s a known patient, do that. Results drive it. That will reduce the number of tests that are done without in any way being of detriment to the patient or the quality of care.”
To conduct this study, Dr Singh and his colleagues reviewed the history of 237 patients, ages 19 to 87, who had a total of 1503 episodes of testing.
In addition to SPEP, many patients had serum immunofixation electrophoresis and/or serum free light chain assays.
But the researchers found that only 46% of the serum immunofixation and 42% of the serum free light chain assays were warranted.
The 2 tests were ordered multiple times in patients in whom M-protein was easily detected with SPEP. In fact, for most patients with measurable levels of M-protein, SPEP can be used to follow the course of the disease and treatment, the researchers said.
“About 40% to 50% of the second tests are not needed or adding value,” Dr Sing stressed.
In fact, he and his colleagues estimated that putting an end to unnecessary testing would have saved $64,182.95 per year in healthcare costs at this institution.
Therefore, the researchers propose using an algorithm that would put more of the decision-making in the hands of pathologists interpreting the tests.
An example of when serum immunofixation and serum free light chain assays should be done at least once is in a new patient when M-protein is first found, Dr Singh said. The additional tests might also be beneficial for patients under treatment for multiple myeloma, to ensure there are no trace amounts left of the abnormal protein.
Dr Singh added that testing patterns similar to those observed in this study are in play in hospitals across the US. However, a protocol similar to the one he is proposing has safely enabled up to a 60% reduction in the volume of second tests at a Missouri hospital where it has been in use for about 8 years.
“It’s better for patients and for healthcare delivery in general,” Dr Singh said. “Why spend money that you don’t need to spend when you are not gaining information that will benefit the patient’s outcome?”
Inflammation has negative effects on HSCs
in the bone marrow
Preclinical research suggests chronic inflammation leads to an imbalanced blood system, which may have an impact on hematopoietic stem cell (HSC) transplant.
The study showed that chronic exposure to an inflammatory “emergency” signal, interleukin-1 (IL-1), has a negative effect on HSCs—restricting differentiation, impairing self-renewal capacity, and priming HSCs to fail massive replicative challenges such as transplantation.
However, these effects proved to be fully reversible.
Eric M. Pietras, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues recounted these findings in Nature Cell Biology.
While HSCs are usually dormant in the bone marrow, Dr Pietras said he and his colleagues showed that, “these cells are also exquisitely sensitive to changes in their environment and react accordingly.”
The team showed that HSCs are sensitive to the amount of IL-1 they encounter. Chronic IL-1 exposure prompts accelerated cell division and pushes HSCs toward myeloid differentiation through activation of the NF-κB pathway and engagement of a PU.1-dependent myeloid gene program.
So HSCs that are overexposed to IL-1 lose their ability to differentiate into lymphoid and erythroid cells.
“[The HSCs are] receiving a signal telling them they need to keep building myeloid cells, and, as a result, they don’t make the other blood cells you need,” Dr Pietras explained.
“You can end up with too few red blood cells, reducing the body’s ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed, and even aged, blood systems.”
Chronic IL-1 exposure also led to decreased self-renewal activity and regenerative potential in HSCs in response to transplantation in mice. Dr Pietras and his colleagues believe these findings may translate to HSC transplant in humans.
“Our results show that not only should we be looking for markers of blood system compatibility [in HSC donors], but we may also want to explore whether a potential donor’s [HSCs] have been exposed to inflammation and may not be as effective at rebuilding the patient’s blood system,” Dr Pietras said.
“Likewise, the presence of inflammation in the individual receiving the [HSC transplant] could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.”
Fortunately, Dr Pietras and his colleagues found the damaging effects of chronic IL-1 exposure could be reversed upon IL-1 withdrawal.
To test the durability of IL-1’s effects, the researchers treated mice with IL-1 for 20 days and then stopped for several weeks to see if the HSCs recovered.
“Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on [HSCs], perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,” Dr Pietras said.
“Of course, we don’t yet know, on a human scale, how long it takes a stem cell to ‘remember’ these insults. It may be that, after a longer period of exposure to IL-1, these changes become more fixed.”
in the bone marrow
Preclinical research suggests chronic inflammation leads to an imbalanced blood system, which may have an impact on hematopoietic stem cell (HSC) transplant.
The study showed that chronic exposure to an inflammatory “emergency” signal, interleukin-1 (IL-1), has a negative effect on HSCs—restricting differentiation, impairing self-renewal capacity, and priming HSCs to fail massive replicative challenges such as transplantation.
However, these effects proved to be fully reversible.
Eric M. Pietras, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues recounted these findings in Nature Cell Biology.
While HSCs are usually dormant in the bone marrow, Dr Pietras said he and his colleagues showed that, “these cells are also exquisitely sensitive to changes in their environment and react accordingly.”
The team showed that HSCs are sensitive to the amount of IL-1 they encounter. Chronic IL-1 exposure prompts accelerated cell division and pushes HSCs toward myeloid differentiation through activation of the NF-κB pathway and engagement of a PU.1-dependent myeloid gene program.
So HSCs that are overexposed to IL-1 lose their ability to differentiate into lymphoid and erythroid cells.
“[The HSCs are] receiving a signal telling them they need to keep building myeloid cells, and, as a result, they don’t make the other blood cells you need,” Dr Pietras explained.
“You can end up with too few red blood cells, reducing the body’s ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed, and even aged, blood systems.”
Chronic IL-1 exposure also led to decreased self-renewal activity and regenerative potential in HSCs in response to transplantation in mice. Dr Pietras and his colleagues believe these findings may translate to HSC transplant in humans.
“Our results show that not only should we be looking for markers of blood system compatibility [in HSC donors], but we may also want to explore whether a potential donor’s [HSCs] have been exposed to inflammation and may not be as effective at rebuilding the patient’s blood system,” Dr Pietras said.
“Likewise, the presence of inflammation in the individual receiving the [HSC transplant] could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.”
Fortunately, Dr Pietras and his colleagues found the damaging effects of chronic IL-1 exposure could be reversed upon IL-1 withdrawal.
To test the durability of IL-1’s effects, the researchers treated mice with IL-1 for 20 days and then stopped for several weeks to see if the HSCs recovered.
“Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on [HSCs], perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,” Dr Pietras said.
“Of course, we don’t yet know, on a human scale, how long it takes a stem cell to ‘remember’ these insults. It may be that, after a longer period of exposure to IL-1, these changes become more fixed.”
in the bone marrow
Preclinical research suggests chronic inflammation leads to an imbalanced blood system, which may have an impact on hematopoietic stem cell (HSC) transplant.
The study showed that chronic exposure to an inflammatory “emergency” signal, interleukin-1 (IL-1), has a negative effect on HSCs—restricting differentiation, impairing self-renewal capacity, and priming HSCs to fail massive replicative challenges such as transplantation.
However, these effects proved to be fully reversible.
Eric M. Pietras, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues recounted these findings in Nature Cell Biology.
While HSCs are usually dormant in the bone marrow, Dr Pietras said he and his colleagues showed that, “these cells are also exquisitely sensitive to changes in their environment and react accordingly.”
The team showed that HSCs are sensitive to the amount of IL-1 they encounter. Chronic IL-1 exposure prompts accelerated cell division and pushes HSCs toward myeloid differentiation through activation of the NF-κB pathway and engagement of a PU.1-dependent myeloid gene program.
So HSCs that are overexposed to IL-1 lose their ability to differentiate into lymphoid and erythroid cells.
“[The HSCs are] receiving a signal telling them they need to keep building myeloid cells, and, as a result, they don’t make the other blood cells you need,” Dr Pietras explained.
“You can end up with too few red blood cells, reducing the body’s ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed, and even aged, blood systems.”
Chronic IL-1 exposure also led to decreased self-renewal activity and regenerative potential in HSCs in response to transplantation in mice. Dr Pietras and his colleagues believe these findings may translate to HSC transplant in humans.
“Our results show that not only should we be looking for markers of blood system compatibility [in HSC donors], but we may also want to explore whether a potential donor’s [HSCs] have been exposed to inflammation and may not be as effective at rebuilding the patient’s blood system,” Dr Pietras said.
“Likewise, the presence of inflammation in the individual receiving the [HSC transplant] could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.”
Fortunately, Dr Pietras and his colleagues found the damaging effects of chronic IL-1 exposure could be reversed upon IL-1 withdrawal.
To test the durability of IL-1’s effects, the researchers treated mice with IL-1 for 20 days and then stopped for several weeks to see if the HSCs recovered.
“Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on [HSCs], perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,” Dr Pietras said.
“Of course, we don’t yet know, on a human scale, how long it takes a stem cell to ‘remember’ these insults. It may be that, after a longer period of exposure to IL-1, these changes become more fixed.”
CDC, OSHA issue guidance to protect workers from Zika virus
Photo by William Weinert
The US Centers for Disease Control and Prevention (CDC) and the Occupational Safety and Health Administration (OSHA) have issued an interim guidance for protecting workers from occupational exposure to the Zika virus.
The guidance is for healthcare and laboratory workers, outdoor workers, mosquito control workers, and business travelers.
It includes recommendations to help protect these workers from mosquito bites and exposure to an infected person’s blood or other body fluids.
The CDC noted that, although Zika virus is primarily spread by infected mosquitoes, exposure to an infected person’s blood or other body fluids may also result in transmission.
So healthcare workers who may be exposed to contaminated blood or other potentially infectious materials from people infected with Zika virus may require additional protection.
Recommendations for healthcare and laboratory workers
Employers and workers in healthcare settings and laboratories should follow standard infection control and biosafety practices (including universal precautions) as appropriate to prevent or minimize the risk of Zika virus transmission.
Standard precautions include, but are not limited to, hand hygiene and the use of personal protective equipment (PPE) to avoid direct contact with blood and other potentially infectious materials, including laboratory specimens/samples. PPE may include gloves, gowns, masks, and eye protection.
Hand hygiene consists of washing with soap and water or using alcohol-based hand rubs containing at least 60% alcohol. Soap and water are best for hands that are visibly soiled. Perform hand hygiene before and after any contact with a patient, after any contact with potentially infectious material, and before putting on and upon removing PPE, including gloves.
Laboratories should ensure that their facilities and practices meet the appropriate Biosafety Level for the type of work being conducted (including the specific biologic agents—in this case, Zika virus) in the laboratory.
Employers should ensure that workers follow workplace standard operating procedures (eg, workplace exposure control plans) and use the engineering controls and work practices available in the workplace to prevent exposure to blood or other potentially infectious materials.
Employers should ensure workers do not bend, recap, or remove contaminated needles or other contaminated sharps. Properly dispose of these items in closable, puncture-resistant, leak-proof, and labeled or color-coded containers. Workers should use sharps with engineered sharps injury protection to avoid sharps-related injuries.
Additional details and recommendations for business travelers, outdoor workers, and mosquito control workers are available in the full guidance document.
The CDC said it will continue to update this guidance based on accumulating evidence. For updates, visit www.cdc.gov/zika.
Photo by William Weinert
The US Centers for Disease Control and Prevention (CDC) and the Occupational Safety and Health Administration (OSHA) have issued an interim guidance for protecting workers from occupational exposure to the Zika virus.
The guidance is for healthcare and laboratory workers, outdoor workers, mosquito control workers, and business travelers.
It includes recommendations to help protect these workers from mosquito bites and exposure to an infected person’s blood or other body fluids.
The CDC noted that, although Zika virus is primarily spread by infected mosquitoes, exposure to an infected person’s blood or other body fluids may also result in transmission.
So healthcare workers who may be exposed to contaminated blood or other potentially infectious materials from people infected with Zika virus may require additional protection.
Recommendations for healthcare and laboratory workers
Employers and workers in healthcare settings and laboratories should follow standard infection control and biosafety practices (including universal precautions) as appropriate to prevent or minimize the risk of Zika virus transmission.
Standard precautions include, but are not limited to, hand hygiene and the use of personal protective equipment (PPE) to avoid direct contact with blood and other potentially infectious materials, including laboratory specimens/samples. PPE may include gloves, gowns, masks, and eye protection.
Hand hygiene consists of washing with soap and water or using alcohol-based hand rubs containing at least 60% alcohol. Soap and water are best for hands that are visibly soiled. Perform hand hygiene before and after any contact with a patient, after any contact with potentially infectious material, and before putting on and upon removing PPE, including gloves.
Laboratories should ensure that their facilities and practices meet the appropriate Biosafety Level for the type of work being conducted (including the specific biologic agents—in this case, Zika virus) in the laboratory.
Employers should ensure that workers follow workplace standard operating procedures (eg, workplace exposure control plans) and use the engineering controls and work practices available in the workplace to prevent exposure to blood or other potentially infectious materials.
Employers should ensure workers do not bend, recap, or remove contaminated needles or other contaminated sharps. Properly dispose of these items in closable, puncture-resistant, leak-proof, and labeled or color-coded containers. Workers should use sharps with engineered sharps injury protection to avoid sharps-related injuries.
Additional details and recommendations for business travelers, outdoor workers, and mosquito control workers are available in the full guidance document.
The CDC said it will continue to update this guidance based on accumulating evidence. For updates, visit www.cdc.gov/zika.
Photo by William Weinert
The US Centers for Disease Control and Prevention (CDC) and the Occupational Safety and Health Administration (OSHA) have issued an interim guidance for protecting workers from occupational exposure to the Zika virus.
The guidance is for healthcare and laboratory workers, outdoor workers, mosquito control workers, and business travelers.
It includes recommendations to help protect these workers from mosquito bites and exposure to an infected person’s blood or other body fluids.
The CDC noted that, although Zika virus is primarily spread by infected mosquitoes, exposure to an infected person’s blood or other body fluids may also result in transmission.
So healthcare workers who may be exposed to contaminated blood or other potentially infectious materials from people infected with Zika virus may require additional protection.
Recommendations for healthcare and laboratory workers
Employers and workers in healthcare settings and laboratories should follow standard infection control and biosafety practices (including universal precautions) as appropriate to prevent or minimize the risk of Zika virus transmission.
Standard precautions include, but are not limited to, hand hygiene and the use of personal protective equipment (PPE) to avoid direct contact with blood and other potentially infectious materials, including laboratory specimens/samples. PPE may include gloves, gowns, masks, and eye protection.
Hand hygiene consists of washing with soap and water or using alcohol-based hand rubs containing at least 60% alcohol. Soap and water are best for hands that are visibly soiled. Perform hand hygiene before and after any contact with a patient, after any contact with potentially infectious material, and before putting on and upon removing PPE, including gloves.
Laboratories should ensure that their facilities and practices meet the appropriate Biosafety Level for the type of work being conducted (including the specific biologic agents—in this case, Zika virus) in the laboratory.
Employers should ensure that workers follow workplace standard operating procedures (eg, workplace exposure control plans) and use the engineering controls and work practices available in the workplace to prevent exposure to blood or other potentially infectious materials.
Employers should ensure workers do not bend, recap, or remove contaminated needles or other contaminated sharps. Properly dispose of these items in closable, puncture-resistant, leak-proof, and labeled or color-coded containers. Workers should use sharps with engineered sharps injury protection to avoid sharps-related injuries.
Additional details and recommendations for business travelers, outdoor workers, and mosquito control workers are available in the full guidance document.
The CDC said it will continue to update this guidance based on accumulating evidence. For updates, visit www.cdc.gov/zika.
Combo may be active in refractory MM
Photo courtesy of the CDC
The combination of vorinostat and bortezomib, with or without dexamethasone, can be active in patients with multiple myeloma (MM) that is refractory to novel treatments, according to researchers.
In a phase 2 trial, the combination produced an overall response rate of 11% among MM patients who were refractory to bortezomib and were either refractory to or could not receive treatment with an immunomodulatory agent (IMiD).
About 92% of patients had drug-related adverse events (AEs), and 20% had serious drug-related AEs.
These results were published in Clinical Lymphoma, Myeloma & Leukemia. The study was funded by Merck & Co., Inc., which markets vorinostat as Zolinza.
This trial (VANTAGE 095) enrolled 143 MM patients from 41 centers in 12 countries. The patients had a median age of 63 (range, 37-81) and had received a median of 4 prior lines of therapy (range, 2-17).
All 143 patients were considered refractory to previous bortezomib, which was defined as less than 25% response on therapy or progression during/less than 60 days after the completion of bortezomib therapy.
All but 1 patient had been exposed to 1 or more IMiDs (99.3%). Roughly 87% of patients exposed to IMiDs were considered to have disease refractory to at least 1 IMiD and 40% to at least 2 different IMiDs. Three percent of patients were considered ineligible for further IMiD-based therapy because of previous toxicities.
For this study, patients received 21-day cycles of bortezomib (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) plus oral vorinostat at 400 mg/d on days 1 to 14.
If a patient had no change as the best response after 4 cycles of treatment or progressive disease after 2 cycles of treatment, oral dexamethasone at 20 mg on the day of and day after each dose of bortezomib could be added to the treatment regimen.
Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study.
One hundred and forty-two patients were evaluable for safety and efficacy. Fifty-seven of these patients received dexamethasone per protocol.
The overall response rate (partial response or better), as assessed by an independent adjudication committee, was 11.3%.
All 16 responses were partial responses. The median time to response was 44 days (range, 22-71), and the median duration of response was 211 days (range, 64-550 days).
Eleven patients (7.7%) had a minimal response, and 87 (61.3%) had stable disease.
The median progression-free survival was 3.13 months, and the median time to progression was 3.47 months. The median overall survival was 11.2 months, with a 2-year survival rate of 32%.
All 142 patients had at least 1 AE, and 131 (92.3%) had drug-related AEs. Most AEs were grade 3 (28.9%) or 4 (50.7%). Serious AEs occurred in 64.8% of patients, and serious drug-related AEs occurred in 20.4%.
Twenty-seven patients (19%) discontinued treatment due to an AE. And 24 patients (16.9%) died from an AE, although 18 of these deaths were attributable to progression of underlying MM.
The most common AEs were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%).
Photo courtesy of the CDC
The combination of vorinostat and bortezomib, with or without dexamethasone, can be active in patients with multiple myeloma (MM) that is refractory to novel treatments, according to researchers.
In a phase 2 trial, the combination produced an overall response rate of 11% among MM patients who were refractory to bortezomib and were either refractory to or could not receive treatment with an immunomodulatory agent (IMiD).
About 92% of patients had drug-related adverse events (AEs), and 20% had serious drug-related AEs.
These results were published in Clinical Lymphoma, Myeloma & Leukemia. The study was funded by Merck & Co., Inc., which markets vorinostat as Zolinza.
This trial (VANTAGE 095) enrolled 143 MM patients from 41 centers in 12 countries. The patients had a median age of 63 (range, 37-81) and had received a median of 4 prior lines of therapy (range, 2-17).
All 143 patients were considered refractory to previous bortezomib, which was defined as less than 25% response on therapy or progression during/less than 60 days after the completion of bortezomib therapy.
All but 1 patient had been exposed to 1 or more IMiDs (99.3%). Roughly 87% of patients exposed to IMiDs were considered to have disease refractory to at least 1 IMiD and 40% to at least 2 different IMiDs. Three percent of patients were considered ineligible for further IMiD-based therapy because of previous toxicities.
For this study, patients received 21-day cycles of bortezomib (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) plus oral vorinostat at 400 mg/d on days 1 to 14.
If a patient had no change as the best response after 4 cycles of treatment or progressive disease after 2 cycles of treatment, oral dexamethasone at 20 mg on the day of and day after each dose of bortezomib could be added to the treatment regimen.
Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study.
One hundred and forty-two patients were evaluable for safety and efficacy. Fifty-seven of these patients received dexamethasone per protocol.
The overall response rate (partial response or better), as assessed by an independent adjudication committee, was 11.3%.
All 16 responses were partial responses. The median time to response was 44 days (range, 22-71), and the median duration of response was 211 days (range, 64-550 days).
Eleven patients (7.7%) had a minimal response, and 87 (61.3%) had stable disease.
The median progression-free survival was 3.13 months, and the median time to progression was 3.47 months. The median overall survival was 11.2 months, with a 2-year survival rate of 32%.
All 142 patients had at least 1 AE, and 131 (92.3%) had drug-related AEs. Most AEs were grade 3 (28.9%) or 4 (50.7%). Serious AEs occurred in 64.8% of patients, and serious drug-related AEs occurred in 20.4%.
Twenty-seven patients (19%) discontinued treatment due to an AE. And 24 patients (16.9%) died from an AE, although 18 of these deaths were attributable to progression of underlying MM.
The most common AEs were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%).
Photo courtesy of the CDC
The combination of vorinostat and bortezomib, with or without dexamethasone, can be active in patients with multiple myeloma (MM) that is refractory to novel treatments, according to researchers.
In a phase 2 trial, the combination produced an overall response rate of 11% among MM patients who were refractory to bortezomib and were either refractory to or could not receive treatment with an immunomodulatory agent (IMiD).
About 92% of patients had drug-related adverse events (AEs), and 20% had serious drug-related AEs.
These results were published in Clinical Lymphoma, Myeloma & Leukemia. The study was funded by Merck & Co., Inc., which markets vorinostat as Zolinza.
This trial (VANTAGE 095) enrolled 143 MM patients from 41 centers in 12 countries. The patients had a median age of 63 (range, 37-81) and had received a median of 4 prior lines of therapy (range, 2-17).
All 143 patients were considered refractory to previous bortezomib, which was defined as less than 25% response on therapy or progression during/less than 60 days after the completion of bortezomib therapy.
All but 1 patient had been exposed to 1 or more IMiDs (99.3%). Roughly 87% of patients exposed to IMiDs were considered to have disease refractory to at least 1 IMiD and 40% to at least 2 different IMiDs. Three percent of patients were considered ineligible for further IMiD-based therapy because of previous toxicities.
For this study, patients received 21-day cycles of bortezomib (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) plus oral vorinostat at 400 mg/d on days 1 to 14.
If a patient had no change as the best response after 4 cycles of treatment or progressive disease after 2 cycles of treatment, oral dexamethasone at 20 mg on the day of and day after each dose of bortezomib could be added to the treatment regimen.
Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study.
One hundred and forty-two patients were evaluable for safety and efficacy. Fifty-seven of these patients received dexamethasone per protocol.
The overall response rate (partial response or better), as assessed by an independent adjudication committee, was 11.3%.
All 16 responses were partial responses. The median time to response was 44 days (range, 22-71), and the median duration of response was 211 days (range, 64-550 days).
Eleven patients (7.7%) had a minimal response, and 87 (61.3%) had stable disease.
The median progression-free survival was 3.13 months, and the median time to progression was 3.47 months. The median overall survival was 11.2 months, with a 2-year survival rate of 32%.
All 142 patients had at least 1 AE, and 131 (92.3%) had drug-related AEs. Most AEs were grade 3 (28.9%) or 4 (50.7%). Serious AEs occurred in 64.8% of patients, and serious drug-related AEs occurred in 20.4%.
Twenty-seven patients (19%) discontinued treatment due to an AE. And 24 patients (16.9%) died from an AE, although 18 of these deaths were attributable to progression of underlying MM.
The most common AEs were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%).
Factors may increase risk of asparaginase-induced pancreatitis in ALL
(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
Combo could improve treatment of MM, team says
multiple myeloma
Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.
The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.
And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.
Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.
First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.
Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.
When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.
The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.
However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.
Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.
In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.
The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.
The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.
multiple myeloma
Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.
The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.
And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.
Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.
First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.
Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.
When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.
The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.
However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.
Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.
In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.
The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.
The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.
multiple myeloma
Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.
The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.
And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.
Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.
First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.
Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.
When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.
The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.
However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.
Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.
In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.
The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.
The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.
Drug corrects anemia in CKD patients
The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.
Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with
erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.
In addition, researchers said there were no serious adverse events related to roxadustat.
Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.
The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.
Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.
In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.
The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.
Results
Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).
Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.
Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.
Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).
After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).
“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”
“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”
Treatment-emergent adverse events were reported in 80% of all patients.
The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).
The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.
Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with
erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.
In addition, researchers said there were no serious adverse events related to roxadustat.
Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.
The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.
Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.
In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.
The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.
Results
Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).
Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.
Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.
Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).
After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).
“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”
“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”
Treatment-emergent adverse events were reported in 80% of all patients.
The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).
The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.
Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with
erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.
In addition, researchers said there were no serious adverse events related to roxadustat.
Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.
The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.
Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.
In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.
The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.
Results
Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).
Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.
Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.
Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).
After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).
“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”
“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”
Treatment-emergent adverse events were reported in 80% of all patients.
The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).
NIH stops production at 2 facilities
Photo by Daniel Sone
The National Institutes of Health (NIH) has suspended production in 2 of its facilities—a National Cancer Institute (NCI) laboratory engaged in the production of cell therapies and a National Institute of Mental Health facility producing positron emission tomography (PET) materials.
Last year, an inspection by the US Food and Drug Administration revealed problems with facilities, equipment, procedures, and training in the NIH Clinical Center Pharmaceutical Development Section (PDS), which is responsible for managing investigational drugs.
So the NIH closed the sterile production unit of the PDS and hired 2 companies specializing in quality assurance for manufacturing and compounding—Working Buildings and Clinical IQ—to evaluate all NIH facilities producing sterile or infused products for administration to research participants.
This review is still underway, and preliminary findings have identified facilities not in compliance with quality and safety standards, and not suitable for the production of sterile or infused products.
As a result, the NIH suspended production in the aforementioned facilities manufacturing cell therapy and PET materials.
The NIH said there is no evidence that any patients have been harmed, but a rigorous clinical review will be conducted. And the NIH will not enroll new patients in affected trials until the issues are resolved.
The NCI facility produces cell therapies in cooperation with Kite Pharma, Inc. The company and the NCI are advancing multiple clinical trials under Cooperative Research and Development Agreements for the treatment of hematologic malignancies and solid tumors.
Patients currently enrolled in ongoing NCI trials of cell therapy will continue to receive treatment, but no new patients will be enrolled until the review is complete.
And Kite Pharma said its 4 trials of the chimeric antigen receptor T-cell therapy KTE-C19 will continue. This includes:
ZUMA-1—KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma
ZUMA-2—KTE-C19 in patients with relapsed/refractory mantle cell lymphoma
ZUMA-3—KTE-C19 in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia
ZUMA-4—KTE-C19 in pediatric and adolescent patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.
The company stressed that the review of the NCI’s manufacturing facilities is not related to KTE-C19 or Kite’s manufacturing capabilities.
Photo by Daniel Sone
The National Institutes of Health (NIH) has suspended production in 2 of its facilities—a National Cancer Institute (NCI) laboratory engaged in the production of cell therapies and a National Institute of Mental Health facility producing positron emission tomography (PET) materials.
Last year, an inspection by the US Food and Drug Administration revealed problems with facilities, equipment, procedures, and training in the NIH Clinical Center Pharmaceutical Development Section (PDS), which is responsible for managing investigational drugs.
So the NIH closed the sterile production unit of the PDS and hired 2 companies specializing in quality assurance for manufacturing and compounding—Working Buildings and Clinical IQ—to evaluate all NIH facilities producing sterile or infused products for administration to research participants.
This review is still underway, and preliminary findings have identified facilities not in compliance with quality and safety standards, and not suitable for the production of sterile or infused products.
As a result, the NIH suspended production in the aforementioned facilities manufacturing cell therapy and PET materials.
The NIH said there is no evidence that any patients have been harmed, but a rigorous clinical review will be conducted. And the NIH will not enroll new patients in affected trials until the issues are resolved.
The NCI facility produces cell therapies in cooperation with Kite Pharma, Inc. The company and the NCI are advancing multiple clinical trials under Cooperative Research and Development Agreements for the treatment of hematologic malignancies and solid tumors.
Patients currently enrolled in ongoing NCI trials of cell therapy will continue to receive treatment, but no new patients will be enrolled until the review is complete.
And Kite Pharma said its 4 trials of the chimeric antigen receptor T-cell therapy KTE-C19 will continue. This includes:
ZUMA-1—KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma
ZUMA-2—KTE-C19 in patients with relapsed/refractory mantle cell lymphoma
ZUMA-3—KTE-C19 in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia
ZUMA-4—KTE-C19 in pediatric and adolescent patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.
The company stressed that the review of the NCI’s manufacturing facilities is not related to KTE-C19 or Kite’s manufacturing capabilities.
Photo by Daniel Sone
The National Institutes of Health (NIH) has suspended production in 2 of its facilities—a National Cancer Institute (NCI) laboratory engaged in the production of cell therapies and a National Institute of Mental Health facility producing positron emission tomography (PET) materials.
Last year, an inspection by the US Food and Drug Administration revealed problems with facilities, equipment, procedures, and training in the NIH Clinical Center Pharmaceutical Development Section (PDS), which is responsible for managing investigational drugs.
So the NIH closed the sterile production unit of the PDS and hired 2 companies specializing in quality assurance for manufacturing and compounding—Working Buildings and Clinical IQ—to evaluate all NIH facilities producing sterile or infused products for administration to research participants.
This review is still underway, and preliminary findings have identified facilities not in compliance with quality and safety standards, and not suitable for the production of sterile or infused products.
As a result, the NIH suspended production in the aforementioned facilities manufacturing cell therapy and PET materials.
The NIH said there is no evidence that any patients have been harmed, but a rigorous clinical review will be conducted. And the NIH will not enroll new patients in affected trials until the issues are resolved.
The NCI facility produces cell therapies in cooperation with Kite Pharma, Inc. The company and the NCI are advancing multiple clinical trials under Cooperative Research and Development Agreements for the treatment of hematologic malignancies and solid tumors.
Patients currently enrolled in ongoing NCI trials of cell therapy will continue to receive treatment, but no new patients will be enrolled until the review is complete.
And Kite Pharma said its 4 trials of the chimeric antigen receptor T-cell therapy KTE-C19 will continue. This includes:
ZUMA-1—KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma
ZUMA-2—KTE-C19 in patients with relapsed/refractory mantle cell lymphoma
ZUMA-3—KTE-C19 in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia
ZUMA-4—KTE-C19 in pediatric and adolescent patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.
The company stressed that the review of the NCI’s manufacturing facilities is not related to KTE-C19 or Kite’s manufacturing capabilities.
HHS provides funding for trial of Zika test
Photo by Juan D. Alfonso
The US Department of Health and Human Services (HHS) is providing financial support for a clinical trial of the cobas® Zika test, which is designed to screen blood donations for Zika virus.
The US Food and Drug Administration (FDA) recently authorized the use of this test, under an investigational new drug application protocol, for screening donated blood in areas with active, mosquito-borne transmission of Zika virus.
This means the cobas® Zika test can be used by US blood screening laboratories, but the laboratories will need to be enrolled in and contracted into the clinical trial as specified and agreed with the FDA’s Center for Biologics Evaluation and Research.
Now, the HHS has announced that the Biomedical Advanced Research and Development Authority (BARDA) is supporting the trial, which will evaluate the sensitivity and specificity of the test in its actual use.
The trial is necessary for Roche, the company developing the cobas® Zika test, to apply for FDA approval for commercial marketing.
“BARDA staff has worked closely with our partners at FDA and the Office of the Assistant Secretary of Health to ensure the continuity and safety of the US blood supply,” said Richard Hatchett, BARDA’s acting director.
“Today’s award to Roche is an important step towards securing the safety of the blood supply in Puerto Rico and in the rest of the United States.”
Under the 1-year, $354,500 contract, Roche will study blood samples to confirm whether the test accurately and reliably detects and identifies Zika virus, even when present in very low concentrations in donor blood.
Photo by Juan D. Alfonso
The US Department of Health and Human Services (HHS) is providing financial support for a clinical trial of the cobas® Zika test, which is designed to screen blood donations for Zika virus.
The US Food and Drug Administration (FDA) recently authorized the use of this test, under an investigational new drug application protocol, for screening donated blood in areas with active, mosquito-borne transmission of Zika virus.
This means the cobas® Zika test can be used by US blood screening laboratories, but the laboratories will need to be enrolled in and contracted into the clinical trial as specified and agreed with the FDA’s Center for Biologics Evaluation and Research.
Now, the HHS has announced that the Biomedical Advanced Research and Development Authority (BARDA) is supporting the trial, which will evaluate the sensitivity and specificity of the test in its actual use.
The trial is necessary for Roche, the company developing the cobas® Zika test, to apply for FDA approval for commercial marketing.
“BARDA staff has worked closely with our partners at FDA and the Office of the Assistant Secretary of Health to ensure the continuity and safety of the US blood supply,” said Richard Hatchett, BARDA’s acting director.
“Today’s award to Roche is an important step towards securing the safety of the blood supply in Puerto Rico and in the rest of the United States.”
Under the 1-year, $354,500 contract, Roche will study blood samples to confirm whether the test accurately and reliably detects and identifies Zika virus, even when present in very low concentrations in donor blood.
Photo by Juan D. Alfonso
The US Department of Health and Human Services (HHS) is providing financial support for a clinical trial of the cobas® Zika test, which is designed to screen blood donations for Zika virus.
The US Food and Drug Administration (FDA) recently authorized the use of this test, under an investigational new drug application protocol, for screening donated blood in areas with active, mosquito-borne transmission of Zika virus.
This means the cobas® Zika test can be used by US blood screening laboratories, but the laboratories will need to be enrolled in and contracted into the clinical trial as specified and agreed with the FDA’s Center for Biologics Evaluation and Research.
Now, the HHS has announced that the Biomedical Advanced Research and Development Authority (BARDA) is supporting the trial, which will evaluate the sensitivity and specificity of the test in its actual use.
The trial is necessary for Roche, the company developing the cobas® Zika test, to apply for FDA approval for commercial marketing.
“BARDA staff has worked closely with our partners at FDA and the Office of the Assistant Secretary of Health to ensure the continuity and safety of the US blood supply,” said Richard Hatchett, BARDA’s acting director.
“Today’s award to Roche is an important step towards securing the safety of the blood supply in Puerto Rico and in the rest of the United States.”
Under the 1-year, $354,500 contract, Roche will study blood samples to confirm whether the test accurately and reliably detects and identifies Zika virus, even when present in very low concentrations in donor blood.
System reduces risk of transfusion-transmitted malaria
Photo by Daniel Gay
A pathogen-reduction system can safely minimize the risk of malaria transmitted via blood transfusion, according to a randomized trial.
The Mirasol pathogen-reduction technology system uses ultraviolet light energy and riboflavin to reduce the pathogen load and inactivate white blood cells in blood products.
In the current study, the system significantly reduced the transmission of malaria-causing Plasmodium parasites in patients receiving whole blood.
“This is the first study to look at the potential of pathogen-reduction technology in a real-world treatment setting and finds that, although the risk of malaria transmission is not completely eliminated, the risk is severely reduced,” said Jean-Pierre Allain, MD, of the University of Cambridge in the UK.
Dr Allain and his colleagues described this research in The Lancet. The work was funded by TerumoBCT Inc., the company developing the Mirasol system.
The trial included 223 adult patients from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, who required a blood transfusion because of severe anemia or hemorrhage and were expected to remain in the hospital for at least 3 consecutive days after the initial transfusion.
The patients were randomized via computer to receive a transfusion with pathogen-reduced whole blood (treated) or whole blood that was prepared and transfused by standard local practice (untreated). Patients, healthcare providers, and data collectors were blinded to the treatment allocation.
The researchers analyzed blood samples for all of the recipients on the day of the transfusion and 1, 3, 7, and 28 days later. By studying the sequences of Plasmodium genes present in the blood, the team was able to tell whether the patients were likely to be carrying the donor parasite after the transfusion.
In all, 214 patients completed the protocol as planned—107 who received treated blood and 107 who received untreated blood.
A total of 65 patients were not previously carrying a Plasmodium parasite but received parasitemic blood. Twenty-eight of these patients received treated blood, and 37 received untreated blood.
The incidence of transfusion-transmitted malaria was significantly lower for the group that received the treated blood. Twenty-two percent of patients (8/37) who received untreated blood later tested positive for the malaria parasite, compared with 4% (1/28) of patients who received treated blood (P=0.039).
The researchers noted that coagulation parameters, platelet counts, and hemostatic status were similar whether patients received treated or untreated blood.
The Mirasol system did not appear to affect the coagulation properties of the blood, and patients who received the treated blood had slightly fewer allergic reactions than those who received the untreated blood (5% vs 8%).
The percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between the groups—43% in the treated-blood group and 39% in the untreated-blood group.
Likewise, there were no significant differences between the groups in the incidence of serious TEAEs (12% vs 8%), life-threatening TEAEs (3% for both), hospital admission (5% vs 4%), or death (7% vs 5%). The researchers noted that none of the deaths were related to transfusion or pathogen-reduction technology.
The team said additional studies of this technology are needed in larger populations—in particular, at-risk populations such as young children and pregnant mothers.
Photo by Daniel Gay
A pathogen-reduction system can safely minimize the risk of malaria transmitted via blood transfusion, according to a randomized trial.
The Mirasol pathogen-reduction technology system uses ultraviolet light energy and riboflavin to reduce the pathogen load and inactivate white blood cells in blood products.
In the current study, the system significantly reduced the transmission of malaria-causing Plasmodium parasites in patients receiving whole blood.
“This is the first study to look at the potential of pathogen-reduction technology in a real-world treatment setting and finds that, although the risk of malaria transmission is not completely eliminated, the risk is severely reduced,” said Jean-Pierre Allain, MD, of the University of Cambridge in the UK.
Dr Allain and his colleagues described this research in The Lancet. The work was funded by TerumoBCT Inc., the company developing the Mirasol system.
The trial included 223 adult patients from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, who required a blood transfusion because of severe anemia or hemorrhage and were expected to remain in the hospital for at least 3 consecutive days after the initial transfusion.
The patients were randomized via computer to receive a transfusion with pathogen-reduced whole blood (treated) or whole blood that was prepared and transfused by standard local practice (untreated). Patients, healthcare providers, and data collectors were blinded to the treatment allocation.
The researchers analyzed blood samples for all of the recipients on the day of the transfusion and 1, 3, 7, and 28 days later. By studying the sequences of Plasmodium genes present in the blood, the team was able to tell whether the patients were likely to be carrying the donor parasite after the transfusion.
In all, 214 patients completed the protocol as planned—107 who received treated blood and 107 who received untreated blood.
A total of 65 patients were not previously carrying a Plasmodium parasite but received parasitemic blood. Twenty-eight of these patients received treated blood, and 37 received untreated blood.
The incidence of transfusion-transmitted malaria was significantly lower for the group that received the treated blood. Twenty-two percent of patients (8/37) who received untreated blood later tested positive for the malaria parasite, compared with 4% (1/28) of patients who received treated blood (P=0.039).
The researchers noted that coagulation parameters, platelet counts, and hemostatic status were similar whether patients received treated or untreated blood.
The Mirasol system did not appear to affect the coagulation properties of the blood, and patients who received the treated blood had slightly fewer allergic reactions than those who received the untreated blood (5% vs 8%).
The percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between the groups—43% in the treated-blood group and 39% in the untreated-blood group.
Likewise, there were no significant differences between the groups in the incidence of serious TEAEs (12% vs 8%), life-threatening TEAEs (3% for both), hospital admission (5% vs 4%), or death (7% vs 5%). The researchers noted that none of the deaths were related to transfusion or pathogen-reduction technology.
The team said additional studies of this technology are needed in larger populations—in particular, at-risk populations such as young children and pregnant mothers.
Photo by Daniel Gay
A pathogen-reduction system can safely minimize the risk of malaria transmitted via blood transfusion, according to a randomized trial.
The Mirasol pathogen-reduction technology system uses ultraviolet light energy and riboflavin to reduce the pathogen load and inactivate white blood cells in blood products.
In the current study, the system significantly reduced the transmission of malaria-causing Plasmodium parasites in patients receiving whole blood.
“This is the first study to look at the potential of pathogen-reduction technology in a real-world treatment setting and finds that, although the risk of malaria transmission is not completely eliminated, the risk is severely reduced,” said Jean-Pierre Allain, MD, of the University of Cambridge in the UK.
Dr Allain and his colleagues described this research in The Lancet. The work was funded by TerumoBCT Inc., the company developing the Mirasol system.
The trial included 223 adult patients from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, who required a blood transfusion because of severe anemia or hemorrhage and were expected to remain in the hospital for at least 3 consecutive days after the initial transfusion.
The patients were randomized via computer to receive a transfusion with pathogen-reduced whole blood (treated) or whole blood that was prepared and transfused by standard local practice (untreated). Patients, healthcare providers, and data collectors were blinded to the treatment allocation.
The researchers analyzed blood samples for all of the recipients on the day of the transfusion and 1, 3, 7, and 28 days later. By studying the sequences of Plasmodium genes present in the blood, the team was able to tell whether the patients were likely to be carrying the donor parasite after the transfusion.
In all, 214 patients completed the protocol as planned—107 who received treated blood and 107 who received untreated blood.
A total of 65 patients were not previously carrying a Plasmodium parasite but received parasitemic blood. Twenty-eight of these patients received treated blood, and 37 received untreated blood.
The incidence of transfusion-transmitted malaria was significantly lower for the group that received the treated blood. Twenty-two percent of patients (8/37) who received untreated blood later tested positive for the malaria parasite, compared with 4% (1/28) of patients who received treated blood (P=0.039).
The researchers noted that coagulation parameters, platelet counts, and hemostatic status were similar whether patients received treated or untreated blood.
The Mirasol system did not appear to affect the coagulation properties of the blood, and patients who received the treated blood had slightly fewer allergic reactions than those who received the untreated blood (5% vs 8%).
The percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between the groups—43% in the treated-blood group and 39% in the untreated-blood group.
Likewise, there were no significant differences between the groups in the incidence of serious TEAEs (12% vs 8%), life-threatening TEAEs (3% for both), hospital admission (5% vs 4%), or death (7% vs 5%). The researchers noted that none of the deaths were related to transfusion or pathogen-reduction technology.
The team said additional studies of this technology are needed in larger populations—in particular, at-risk populations such as young children and pregnant mothers.