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Gut bacteria could help prevent lymphoma, other cancers
New research published in PLOS ONE suggests certain intestinal bacteria could potentially be used to reduce the risk of lymphomas and other cancers.
Researchers believe doctors might be able to reduce a person’s risk of these cancers by analyzing the levels and types of intestinal bacteria in the body and then prescribing probiotics to replace or bolster the amount of bacteria with anti-inflammatory properties.
“It is not invasive and rather easy to do,” said study author Robert Schiestl, PhD, of the University of California, Los Angeles.
Dr Schiestl and his colleagues isolated a bacterium called Lactobacillus johnsonii 456, which is the most abundant of the beneficial bacteria.
The team found this bacterium reduced gene damage and inflammation, which, as they pointed out, plays a key role in cancers and other diseases.
Previous research led by Dr Schiestl presented the first evidence of a relationship between intestinal microbiota and the onset of lymphoma.
The new study explains how this microbiota might delay the onset of cancer and suggests that probiotic supplements could help keep cancer from forming.
For both studies, Dr Schiestl and his team used mice that had mutations in the gene ATM, which made them susceptible to a neurologic disorder called ataxia telangiectasia. The disorder is associated with a high incidence of leukemias, lymphomas, and other cancers.
The mice were divided into two groups—one that was given only anti-inflammatory bacteria and another that received a mix of inflammatory and anti-inflammatory microbes that typically co-exist in the intestines.
With their previous study, Dr Schiestl and his team showed that, in the mice with more of the beneficial bacteria, the lymphoma took significantly longer to form.
For the new study, the researchers analyzed metabolites in the mice’s urine and feces and found the mice that were receiving only the beneficial microbiota produced metabolites that are known to prevent cancer.
Those mice also had more efficient fat and oxidative metabolism, which the researchers believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria, lymphoma formed only half as quickly as it did in the other mice. In addition, mice with the good bacteria lived 4 times longer and had less DNA damage and inflammation.
The researchers said these findings lend credence to the idea that manipulating microbial composition could be used to prevent or alleviate cancer susceptibility. They hope that, in the future, probiotic supplements could be chemopreventive for the average person and decrease tumor incidence in cancer-susceptible populations.
The University of California, Los Angeles has a patent pending on the use of Lactobacillus johnsonii 456 as an anti-inflammatory agent. 
New research published in PLOS ONE suggests certain intestinal bacteria could potentially be used to reduce the risk of lymphomas and other cancers.
Researchers believe doctors might be able to reduce a person’s risk of these cancers by analyzing the levels and types of intestinal bacteria in the body and then prescribing probiotics to replace or bolster the amount of bacteria with anti-inflammatory properties.
“It is not invasive and rather easy to do,” said study author Robert Schiestl, PhD, of the University of California, Los Angeles.
Dr Schiestl and his colleagues isolated a bacterium called Lactobacillus johnsonii 456, which is the most abundant of the beneficial bacteria.
The team found this bacterium reduced gene damage and inflammation, which, as they pointed out, plays a key role in cancers and other diseases.
Previous research led by Dr Schiestl presented the first evidence of a relationship between intestinal microbiota and the onset of lymphoma.
The new study explains how this microbiota might delay the onset of cancer and suggests that probiotic supplements could help keep cancer from forming.
For both studies, Dr Schiestl and his team used mice that had mutations in the gene ATM, which made them susceptible to a neurologic disorder called ataxia telangiectasia. The disorder is associated with a high incidence of leukemias, lymphomas, and other cancers.
The mice were divided into two groups—one that was given only anti-inflammatory bacteria and another that received a mix of inflammatory and anti-inflammatory microbes that typically co-exist in the intestines.
With their previous study, Dr Schiestl and his team showed that, in the mice with more of the beneficial bacteria, the lymphoma took significantly longer to form.
For the new study, the researchers analyzed metabolites in the mice’s urine and feces and found the mice that were receiving only the beneficial microbiota produced metabolites that are known to prevent cancer.
Those mice also had more efficient fat and oxidative metabolism, which the researchers believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria, lymphoma formed only half as quickly as it did in the other mice. In addition, mice with the good bacteria lived 4 times longer and had less DNA damage and inflammation.
The researchers said these findings lend credence to the idea that manipulating microbial composition could be used to prevent or alleviate cancer susceptibility. They hope that, in the future, probiotic supplements could be chemopreventive for the average person and decrease tumor incidence in cancer-susceptible populations.
The University of California, Los Angeles has a patent pending on the use of Lactobacillus johnsonii 456 as an anti-inflammatory agent.
New research published in PLOS ONE suggests certain intestinal bacteria could potentially be used to reduce the risk of lymphomas and other cancers.
Researchers believe doctors might be able to reduce a person’s risk of these cancers by analyzing the levels and types of intestinal bacteria in the body and then prescribing probiotics to replace or bolster the amount of bacteria with anti-inflammatory properties.
“It is not invasive and rather easy to do,” said study author Robert Schiestl, PhD, of the University of California, Los Angeles.
Dr Schiestl and his colleagues isolated a bacterium called Lactobacillus johnsonii 456, which is the most abundant of the beneficial bacteria.
The team found this bacterium reduced gene damage and inflammation, which, as they pointed out, plays a key role in cancers and other diseases.
Previous research led by Dr Schiestl presented the first evidence of a relationship between intestinal microbiota and the onset of lymphoma.
The new study explains how this microbiota might delay the onset of cancer and suggests that probiotic supplements could help keep cancer from forming.
For both studies, Dr Schiestl and his team used mice that had mutations in the gene ATM, which made them susceptible to a neurologic disorder called ataxia telangiectasia. The disorder is associated with a high incidence of leukemias, lymphomas, and other cancers.
The mice were divided into two groups—one that was given only anti-inflammatory bacteria and another that received a mix of inflammatory and anti-inflammatory microbes that typically co-exist in the intestines.
With their previous study, Dr Schiestl and his team showed that, in the mice with more of the beneficial bacteria, the lymphoma took significantly longer to form.
For the new study, the researchers analyzed metabolites in the mice’s urine and feces and found the mice that were receiving only the beneficial microbiota produced metabolites that are known to prevent cancer.
Those mice also had more efficient fat and oxidative metabolism, which the researchers believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria, lymphoma formed only half as quickly as it did in the other mice. In addition, mice with the good bacteria lived 4 times longer and had less DNA damage and inflammation.
The researchers said these findings lend credence to the idea that manipulating microbial composition could be used to prevent or alleviate cancer susceptibility. They hope that, in the future, probiotic supplements could be chemopreventive for the average person and decrease tumor incidence in cancer-susceptible populations.
The University of California, Los Angeles has a patent pending on the use of Lactobacillus johnsonii 456 as an anti-inflammatory agent.
PD-1 inhibitor granted priority review for cHL
Photo courtesy of Business Wire
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application seeking to expand use of the PD-1 inhibitor nivolumab (Opdivo) to patients with previously treated classical Hodgkin lymphoma (cHL).
A priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
About nivolumab
Nivolumab is an inhibitor that binds to the checkpoint receptor PD-1, which is expressed on activated T cells. The drug prevents PD-L1 and PD-L2 from binding, thereby preventing the PD-1 pathway’s suppressive signaling on the immune system, including interference with an anti-tumor immune response.
Nivolumab is being developed by Bristol-Myers Squibb. The drug currently has regulatory approval in 48 countries.
In the US, nivolumab is approved—both as a single agent and in combination—to treat certain patients with melanoma, non-small-cell lung cancer, or advanced renal cell carcinoma.
According to Bristol-Myers Squibb, nivolumab has the potential to become first PD-1 inhibitor approved for a hematologic malignancy in the US.
The supplemental biologics license application for nivolumab included data from the phase 2 trial CheckMate 205. In this ongoing trial, researchers are evaluating nivolumab in patients with relapsed or refractory cHL who have received an autologous stem cell transplant and brentuximab vedotin.
Data from this trial are expected to be presented at a medical meeting later this year.
The FDA previously granted nivolumab breakthrough therapy designation for cHL. The FDA’s breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Photo courtesy of Business Wire
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application seeking to expand use of the PD-1 inhibitor nivolumab (Opdivo) to patients with previously treated classical Hodgkin lymphoma (cHL).
A priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
About nivolumab
Nivolumab is an inhibitor that binds to the checkpoint receptor PD-1, which is expressed on activated T cells. The drug prevents PD-L1 and PD-L2 from binding, thereby preventing the PD-1 pathway’s suppressive signaling on the immune system, including interference with an anti-tumor immune response.
Nivolumab is being developed by Bristol-Myers Squibb. The drug currently has regulatory approval in 48 countries.
In the US, nivolumab is approved—both as a single agent and in combination—to treat certain patients with melanoma, non-small-cell lung cancer, or advanced renal cell carcinoma.
According to Bristol-Myers Squibb, nivolumab has the potential to become first PD-1 inhibitor approved for a hematologic malignancy in the US.
The supplemental biologics license application for nivolumab included data from the phase 2 trial CheckMate 205. In this ongoing trial, researchers are evaluating nivolumab in patients with relapsed or refractory cHL who have received an autologous stem cell transplant and brentuximab vedotin.
Data from this trial are expected to be presented at a medical meeting later this year.
The FDA previously granted nivolumab breakthrough therapy designation for cHL. The FDA’s breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Photo courtesy of Business Wire
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application seeking to expand use of the PD-1 inhibitor nivolumab (Opdivo) to patients with previously treated classical Hodgkin lymphoma (cHL).
A priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
About nivolumab
Nivolumab is an inhibitor that binds to the checkpoint receptor PD-1, which is expressed on activated T cells. The drug prevents PD-L1 and PD-L2 from binding, thereby preventing the PD-1 pathway’s suppressive signaling on the immune system, including interference with an anti-tumor immune response.
Nivolumab is being developed by Bristol-Myers Squibb. The drug currently has regulatory approval in 48 countries.
In the US, nivolumab is approved—both as a single agent and in combination—to treat certain patients with melanoma, non-small-cell lung cancer, or advanced renal cell carcinoma.
According to Bristol-Myers Squibb, nivolumab has the potential to become first PD-1 inhibitor approved for a hematologic malignancy in the US.
The supplemental biologics license application for nivolumab included data from the phase 2 trial CheckMate 205. In this ongoing trial, researchers are evaluating nivolumab in patients with relapsed or refractory cHL who have received an autologous stem cell transplant and brentuximab vedotin.
Data from this trial are expected to be presented at a medical meeting later this year.
The FDA previously granted nivolumab breakthrough therapy designation for cHL. The FDA’s breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Study provides new insight into malaria transmission
infecting a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Research published in PNAS helps explain how the malaria parasite Plasmodium falciparum undergoes the changes that enable transmission of the parasite from humans to mosquitoes.
Investigators determined how the parasite transforms its own structure and the structure of a host red blood cell so the parasite can hide from the body’s normal defenses and later re-enter the bloodstream for transmission via mosquito bite.
The team believes that, by understanding this process, it may be possible to inhibit the blood cell’s transformation.
“Once you understand the molecular mechanisms, it becomes easier to find drugs to target them,” said Sulin Zhang, PhD, of Pennsylvania State University in University Park.
Dr Zhang developed the computational methods used to understand the physical transformations in the infected red blood cells that allow them to avoid removal in the spleen and prepare for transmission to a mosquito host.
He and his colleagues knew that healthy red blood cells are able to squeeze through small slits in the spleen, but damaged and aging red blood cells cannot and are filtered out and removed from the circulation.
To avoid this fate, the sexual stage malaria parasite first makes the red blood cell rigid and hides out in deep tissue. Then, when the parasite is mature, the infected red blood cells become flexible and elastic, ready to be picked up by a mosquito for disease transmission.
To understand these changes, the investigators prepared samples of parasites at each stage and studied the changing microstructure using atomic force microscopy.
This revealed changes in the organization of a meshwork of tiny spring-like proteins in the blood cell membrane. When the parasite is ready for transmission, it reverses the structural changes.
The team then turned to Dr Zhang, who developed a model to explain how subtle changes to the molecular structure of the spring-like proteins were sufficient to make the red blood cell either rigid or flexible.
The investigators are continuing to use Dr Zhang’s model to simulate the overall shapes and the flow dynamics of infected red blood cells in the bloodstream, providing information that could aid researchers looking to inhibit the malaria parasite’s spread.
infecting a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Research published in PNAS helps explain how the malaria parasite Plasmodium falciparum undergoes the changes that enable transmission of the parasite from humans to mosquitoes.
Investigators determined how the parasite transforms its own structure and the structure of a host red blood cell so the parasite can hide from the body’s normal defenses and later re-enter the bloodstream for transmission via mosquito bite.
The team believes that, by understanding this process, it may be possible to inhibit the blood cell’s transformation.
“Once you understand the molecular mechanisms, it becomes easier to find drugs to target them,” said Sulin Zhang, PhD, of Pennsylvania State University in University Park.
Dr Zhang developed the computational methods used to understand the physical transformations in the infected red blood cells that allow them to avoid removal in the spleen and prepare for transmission to a mosquito host.
He and his colleagues knew that healthy red blood cells are able to squeeze through small slits in the spleen, but damaged and aging red blood cells cannot and are filtered out and removed from the circulation.
To avoid this fate, the sexual stage malaria parasite first makes the red blood cell rigid and hides out in deep tissue. Then, when the parasite is mature, the infected red blood cells become flexible and elastic, ready to be picked up by a mosquito for disease transmission.
To understand these changes, the investigators prepared samples of parasites at each stage and studied the changing microstructure using atomic force microscopy.
This revealed changes in the organization of a meshwork of tiny spring-like proteins in the blood cell membrane. When the parasite is ready for transmission, it reverses the structural changes.
The team then turned to Dr Zhang, who developed a model to explain how subtle changes to the molecular structure of the spring-like proteins were sufficient to make the red blood cell either rigid or flexible.
The investigators are continuing to use Dr Zhang’s model to simulate the overall shapes and the flow dynamics of infected red blood cells in the bloodstream, providing information that could aid researchers looking to inhibit the malaria parasite’s spread.
infecting a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Research published in PNAS helps explain how the malaria parasite Plasmodium falciparum undergoes the changes that enable transmission of the parasite from humans to mosquitoes.
Investigators determined how the parasite transforms its own structure and the structure of a host red blood cell so the parasite can hide from the body’s normal defenses and later re-enter the bloodstream for transmission via mosquito bite.
The team believes that, by understanding this process, it may be possible to inhibit the blood cell’s transformation.
“Once you understand the molecular mechanisms, it becomes easier to find drugs to target them,” said Sulin Zhang, PhD, of Pennsylvania State University in University Park.
Dr Zhang developed the computational methods used to understand the physical transformations in the infected red blood cells that allow them to avoid removal in the spleen and prepare for transmission to a mosquito host.
He and his colleagues knew that healthy red blood cells are able to squeeze through small slits in the spleen, but damaged and aging red blood cells cannot and are filtered out and removed from the circulation.
To avoid this fate, the sexual stage malaria parasite first makes the red blood cell rigid and hides out in deep tissue. Then, when the parasite is mature, the infected red blood cells become flexible and elastic, ready to be picked up by a mosquito for disease transmission.
To understand these changes, the investigators prepared samples of parasites at each stage and studied the changing microstructure using atomic force microscopy.
This revealed changes in the organization of a meshwork of tiny spring-like proteins in the blood cell membrane. When the parasite is ready for transmission, it reverses the structural changes.
The team then turned to Dr Zhang, who developed a model to explain how subtle changes to the molecular structure of the spring-like proteins were sufficient to make the red blood cell either rigid or flexible.
The investigators are continuing to use Dr Zhang’s model to simulate the overall shapes and the flow dynamics of infected red blood cells in the bloodstream, providing information that could aid researchers looking to inhibit the malaria parasite’s spread.
TKI trial leaves questions unanswered
Image by Difu Wu
The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.
The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).
The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.
Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.
Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.
However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.
Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.
Problems with ponatinib
Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.
In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.
That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.
EPIC trial
The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.
The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.
Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.
Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).
The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).
All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.
Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).
Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).
Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.
Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.
The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.
Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.
Image by Difu Wu
The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.
The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).
The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.
Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.
Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.
However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.
Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.
Problems with ponatinib
Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.
In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.
That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.
EPIC trial
The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.
The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.
Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.
Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).
The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).
All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.
Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).
Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).
Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.
Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.
The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.
Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.
Image by Difu Wu
The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.
The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).
The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.
Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.
Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.
However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.
Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.
Problems with ponatinib
Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.
In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.
That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.
EPIC trial
The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.
The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.
Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.
Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).
The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).
All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.
Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).
Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).
Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.
Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.
The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.
Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.
CDC says Zika causes microcephaly, other birth defects
Photo by Nina Matthews
After reviewing existing evidence, scientists from the US Centers for Disease Control and Prevention (CDC) have concluded that Zika virus causes
microcephaly and other severe fetal brain defects.
“This study marks a turning point in the Zika outbreak,” said Tom Frieden, MD, director of the CDC.
“It is now clear that the virus causes microcephaly. We’ve now confirmed what mounting evidence has suggested.”
Details on the CDC’s review were published in NEJM.
The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria support the authors’ conclusions.
The finding that Zika virus infection can cause microcephaly and other severe fetal brain defects means that a woman who is infected with Zika during pregnancy has an increased risk of having a baby with these health problems.
However, as we’ve seen during the current Zika outbreak, some infected women deliver babies that appear to be healthy.
The CDC said establishing the causal relationship between Zika and fetal brain defects is an important step in driving additional prevention efforts, focusing research activities, and reinforcing the need for direct communication about the risks of Zika.
However, the agency noted that many questions about the Zika virus remain. And answering these questions will be the focus of ongoing research.
The CDC also said it is not changing its current recommendations regarding the Zika virus. Pregnant women should continue to avoid travel to areas where Zika is actively spreading.
If a pregnant woman travels to or lives in an area with active Zika virus transmission, she should talk with her healthcare provider and take steps to prevent mosquito bites and sexual transmission of the virus.
The CDC also encourages women and their partners in areas with active Zika transmission to engage in pregnancy planning and counseling with their healthcare providers so they know the risks and the ways to mitigate them.
Photo by Nina Matthews
After reviewing existing evidence, scientists from the US Centers for Disease Control and Prevention (CDC) have concluded that Zika virus causes
microcephaly and other severe fetal brain defects.
“This study marks a turning point in the Zika outbreak,” said Tom Frieden, MD, director of the CDC.
“It is now clear that the virus causes microcephaly. We’ve now confirmed what mounting evidence has suggested.”
Details on the CDC’s review were published in NEJM.
The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria support the authors’ conclusions.
The finding that Zika virus infection can cause microcephaly and other severe fetal brain defects means that a woman who is infected with Zika during pregnancy has an increased risk of having a baby with these health problems.
However, as we’ve seen during the current Zika outbreak, some infected women deliver babies that appear to be healthy.
The CDC said establishing the causal relationship between Zika and fetal brain defects is an important step in driving additional prevention efforts, focusing research activities, and reinforcing the need for direct communication about the risks of Zika.
However, the agency noted that many questions about the Zika virus remain. And answering these questions will be the focus of ongoing research.
The CDC also said it is not changing its current recommendations regarding the Zika virus. Pregnant women should continue to avoid travel to areas where Zika is actively spreading.
If a pregnant woman travels to or lives in an area with active Zika virus transmission, she should talk with her healthcare provider and take steps to prevent mosquito bites and sexual transmission of the virus.
The CDC also encourages women and their partners in areas with active Zika transmission to engage in pregnancy planning and counseling with their healthcare providers so they know the risks and the ways to mitigate them.
Photo by Nina Matthews
After reviewing existing evidence, scientists from the US Centers for Disease Control and Prevention (CDC) have concluded that Zika virus causes
microcephaly and other severe fetal brain defects.
“This study marks a turning point in the Zika outbreak,” said Tom Frieden, MD, director of the CDC.
“It is now clear that the virus causes microcephaly. We’ve now confirmed what mounting evidence has suggested.”
Details on the CDC’s review were published in NEJM.
The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria support the authors’ conclusions.
The finding that Zika virus infection can cause microcephaly and other severe fetal brain defects means that a woman who is infected with Zika during pregnancy has an increased risk of having a baby with these health problems.
However, as we’ve seen during the current Zika outbreak, some infected women deliver babies that appear to be healthy.
The CDC said establishing the causal relationship between Zika and fetal brain defects is an important step in driving additional prevention efforts, focusing research activities, and reinforcing the need for direct communication about the risks of Zika.
However, the agency noted that many questions about the Zika virus remain. And answering these questions will be the focus of ongoing research.
The CDC also said it is not changing its current recommendations regarding the Zika virus. Pregnant women should continue to avoid travel to areas where Zika is actively spreading.
If a pregnant woman travels to or lives in an area with active Zika virus transmission, she should talk with her healthcare provider and take steps to prevent mosquito bites and sexual transmission of the virus.
The CDC also encourages women and their partners in areas with active Zika transmission to engage in pregnancy planning and counseling with their healthcare providers so they know the risks and the ways to mitigate them.
Drug appears safe, effective for ocular GVHD
Photo courtesy of
Massachusetts Eye and Ear
A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.
The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.
And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.
These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.
“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.
“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”
The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.
The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.
The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.
Safety/tolerability
There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).
Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).
The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).
There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).
Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.
Efficacy
The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).
Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).
There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).
Schirmer test scores did not change significantly in either treatment group.
ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).
HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).
“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.
“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”
Photo courtesy of
Massachusetts Eye and Ear
A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.
The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.
And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.
These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.
“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.
“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”
The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.
The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.
The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.
Safety/tolerability
There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).
Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).
The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).
There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).
Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.
Efficacy
The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).
Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).
There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).
Schirmer test scores did not change significantly in either treatment group.
ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).
HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).
“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.
“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”
Photo courtesy of
Massachusetts Eye and Ear
A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.
The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.
And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.
These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.
“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.
“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”
The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.
The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.
The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.
Safety/tolerability
There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).
Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).
The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).
There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).
Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.
Efficacy
The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).
Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).
There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).
Schirmer test scores did not change significantly in either treatment group.
ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).
HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).
“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.
“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”
Alternative splicing regulates activity of MALT1
Photo courtesy of
Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.
Photo courtesy of
Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.
Photo courtesy of
Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.
TCD screening underused in sickle cell patients
with sickle cell anemia
Photo courtesy of St. Jude
Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.
However, the rate of TCD screening in these patients falls well below national recommendations.
In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.
Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.
The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.
Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.
The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).
The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).
The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.
This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).
On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).
And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).
The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.
with sickle cell anemia
Photo courtesy of St. Jude
Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.
However, the rate of TCD screening in these patients falls well below national recommendations.
In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.
Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.
The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.
Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.
The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).
The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).
The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.
This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).
On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).
And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).
The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.
with sickle cell anemia
Photo courtesy of St. Jude
Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.
However, the rate of TCD screening in these patients falls well below national recommendations.
In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.
Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.
The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.
Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.
The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).
The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).
The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.
This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).
On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).
And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).
The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.
Company recalls hemostasis valves
Photo courtesy of
Vascular Solutions, Inc.
Vascular Solutions, Inc. has issued a US-wide recall of Guardian II hemostasis valves used in catheterization procedures.
Specific lots of the products have been recalled because they pose an increased risk of air leakage that may lead to an air embolism, which could result in serious injury or death.
This recall only affects the Guardian II hemostasis valves and does not include the Guardian II NC hemostasis valves.
No injuries have been reported in association with this issue to date.
Healthcare facilities that have the affected Guardian II hemostasis valves should remove the products from their inventory and return them to Vascular Solutions.
The recalled products were manufactured from March 2015 to February 2016 and distributed from April 2015 to February 2016.
The recalled products are specific lots of Model Numbers 8210 and 8211. A listing of the recalled lots is available from Vascular Solutions and has been provided to each facility that purchased the affected products.
A total of 26,550 devices have been manufactured, with 5283 distributed in the US. The condition that led to the recall may affect approximately 2.4% of recalled devices.
Vascular Solutions voluntarily initiated the recall on March 3, 2016, through an Urgent Medical Device Recall notification distributed to purchasers of the affected products. The notification identified the specific lots subject to the recall and included instructions on how to return the affected products.
The US Food and Drug Administration (FDA) classified this as a Class I recall. The FDA defines Class I recalls as “a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”
Consumers with questions may contact the company by phone at 1-888-240-6001, Monday through Friday, between the hours of 8:00 am and 5:00 pm Central Time or by email at customerservice@vasc.com.
Adverse reactions or quality problems associated with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Photo courtesy of
Vascular Solutions, Inc.
Vascular Solutions, Inc. has issued a US-wide recall of Guardian II hemostasis valves used in catheterization procedures.
Specific lots of the products have been recalled because they pose an increased risk of air leakage that may lead to an air embolism, which could result in serious injury or death.
This recall only affects the Guardian II hemostasis valves and does not include the Guardian II NC hemostasis valves.
No injuries have been reported in association with this issue to date.
Healthcare facilities that have the affected Guardian II hemostasis valves should remove the products from their inventory and return them to Vascular Solutions.
The recalled products were manufactured from March 2015 to February 2016 and distributed from April 2015 to February 2016.
The recalled products are specific lots of Model Numbers 8210 and 8211. A listing of the recalled lots is available from Vascular Solutions and has been provided to each facility that purchased the affected products.
A total of 26,550 devices have been manufactured, with 5283 distributed in the US. The condition that led to the recall may affect approximately 2.4% of recalled devices.
Vascular Solutions voluntarily initiated the recall on March 3, 2016, through an Urgent Medical Device Recall notification distributed to purchasers of the affected products. The notification identified the specific lots subject to the recall and included instructions on how to return the affected products.
The US Food and Drug Administration (FDA) classified this as a Class I recall. The FDA defines Class I recalls as “a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”
Consumers with questions may contact the company by phone at 1-888-240-6001, Monday through Friday, between the hours of 8:00 am and 5:00 pm Central Time or by email at customerservice@vasc.com.
Adverse reactions or quality problems associated with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Photo courtesy of
Vascular Solutions, Inc.
Vascular Solutions, Inc. has issued a US-wide recall of Guardian II hemostasis valves used in catheterization procedures.
Specific lots of the products have been recalled because they pose an increased risk of air leakage that may lead to an air embolism, which could result in serious injury or death.
This recall only affects the Guardian II hemostasis valves and does not include the Guardian II NC hemostasis valves.
No injuries have been reported in association with this issue to date.
Healthcare facilities that have the affected Guardian II hemostasis valves should remove the products from their inventory and return them to Vascular Solutions.
The recalled products were manufactured from March 2015 to February 2016 and distributed from April 2015 to February 2016.
The recalled products are specific lots of Model Numbers 8210 and 8211. A listing of the recalled lots is available from Vascular Solutions and has been provided to each facility that purchased the affected products.
A total of 26,550 devices have been manufactured, with 5283 distributed in the US. The condition that led to the recall may affect approximately 2.4% of recalled devices.
Vascular Solutions voluntarily initiated the recall on March 3, 2016, through an Urgent Medical Device Recall notification distributed to purchasers of the affected products. The notification identified the specific lots subject to the recall and included instructions on how to return the affected products.
The US Food and Drug Administration (FDA) classified this as a Class I recall. The FDA defines Class I recalls as “a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”
Consumers with questions may contact the company by phone at 1-888-240-6001, Monday through Friday, between the hours of 8:00 am and 5:00 pm Central Time or by email at customerservice@vasc.com.
Adverse reactions or quality problems associated with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Survey says docs don’t know FDA requirements
A survey of nearly 700 US physicians revealed that many do not know the basic requirements for a drug to receive approval from the US Food and
Drug Administration (FDA).
The results also suggested that most physicians don’t understand the FDA’s “breakthrough therapy” designation.
Since 2012, the FDA has been able to designate a drug as a breakthrough therapy if preliminary clinical evidence suggests it provides an advantage
over existing options.
Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues wanted to determine how much physicians understood about this designation and if they had a basic understanding of the FDA’s requirements for drug approval.
So the researchers surveyed internists and specialists from the American Board of Internal Medicine’s diplomate list and reported the results of this survey in JAMA.
Of the 1148 physicians contacted, 692 (60%) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies.
FDA approval
Seventy-three percent of respondents incorrectly believed that, for a drug to gain FDA approval, it must be as effective as drugs that are already approved.
However, 85% of respondents answered correctly that FDA-approved drugs typically have a favorable benefit/harm ratio.
Seventy percent of respondents incorrectly believed that FDA approval requires a drug to have both a statistically significant and a clinically important effect.
Only 6% of respondents knew the correct answer—that neither is required.
Breakthrough designation
Twenty percent of respondents said they were “familiar” (17%) or “very familiar” (3%) with breakthrough therapy designation, while 37% said they were “a little familiar,” and 42% said they were “not familiar at all.”
Fifty-eight percent of respondents said they were “fairly certain” that an FDA-approved breakthrough drug represents a major advance over currently approved treatments for its indication. Thirty-one percent said they were “fairly uncertain,” 5% said they were “very uncertain,” and 6% said they were “very certain.”
Fifty-two percent of respondents incorrectly believed that strong evidence (ie, randomized trials) is needed to earn the breakthrough designation.
However, 45% correctly answered that only preliminary evidence (eg, uncontrolled studies or studies testing surrogate outcomes) is needed. Four percent said very preliminary evidence (eg, in vitro laboratory or animal studies) is needed.
Seventy-seven percent of respondents incorrectly believed that, when the FDA grants breakthrough designation, there is high-quality evidence that the drug is more effective than currently approved treatments.
But 74% of respondents answered correctly that breakthrough designation does not mean there is high-quality evidence that the drug is safer than currently approved treatments.
Dr Kesselheim and his colleagues said the misconceptions identified in this survey may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to patients.
A survey of nearly 700 US physicians revealed that many do not know the basic requirements for a drug to receive approval from the US Food and
Drug Administration (FDA).
The results also suggested that most physicians don’t understand the FDA’s “breakthrough therapy” designation.
Since 2012, the FDA has been able to designate a drug as a breakthrough therapy if preliminary clinical evidence suggests it provides an advantage
over existing options.
Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues wanted to determine how much physicians understood about this designation and if they had a basic understanding of the FDA’s requirements for drug approval.
So the researchers surveyed internists and specialists from the American Board of Internal Medicine’s diplomate list and reported the results of this survey in JAMA.
Of the 1148 physicians contacted, 692 (60%) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies.
FDA approval
Seventy-three percent of respondents incorrectly believed that, for a drug to gain FDA approval, it must be as effective as drugs that are already approved.
However, 85% of respondents answered correctly that FDA-approved drugs typically have a favorable benefit/harm ratio.
Seventy percent of respondents incorrectly believed that FDA approval requires a drug to have both a statistically significant and a clinically important effect.
Only 6% of respondents knew the correct answer—that neither is required.
Breakthrough designation
Twenty percent of respondents said they were “familiar” (17%) or “very familiar” (3%) with breakthrough therapy designation, while 37% said they were “a little familiar,” and 42% said they were “not familiar at all.”
Fifty-eight percent of respondents said they were “fairly certain” that an FDA-approved breakthrough drug represents a major advance over currently approved treatments for its indication. Thirty-one percent said they were “fairly uncertain,” 5% said they were “very uncertain,” and 6% said they were “very certain.”
Fifty-two percent of respondents incorrectly believed that strong evidence (ie, randomized trials) is needed to earn the breakthrough designation.
However, 45% correctly answered that only preliminary evidence (eg, uncontrolled studies or studies testing surrogate outcomes) is needed. Four percent said very preliminary evidence (eg, in vitro laboratory or animal studies) is needed.
Seventy-seven percent of respondents incorrectly believed that, when the FDA grants breakthrough designation, there is high-quality evidence that the drug is more effective than currently approved treatments.
But 74% of respondents answered correctly that breakthrough designation does not mean there is high-quality evidence that the drug is safer than currently approved treatments.
Dr Kesselheim and his colleagues said the misconceptions identified in this survey may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to patients.
A survey of nearly 700 US physicians revealed that many do not know the basic requirements for a drug to receive approval from the US Food and
Drug Administration (FDA).
The results also suggested that most physicians don’t understand the FDA’s “breakthrough therapy” designation.
Since 2012, the FDA has been able to designate a drug as a breakthrough therapy if preliminary clinical evidence suggests it provides an advantage
over existing options.
Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues wanted to determine how much physicians understood about this designation and if they had a basic understanding of the FDA’s requirements for drug approval.
So the researchers surveyed internists and specialists from the American Board of Internal Medicine’s diplomate list and reported the results of this survey in JAMA.
Of the 1148 physicians contacted, 692 (60%) responded. Participants were asked 3 questions about FDA approval and 5 about breakthrough therapies.
FDA approval
Seventy-three percent of respondents incorrectly believed that, for a drug to gain FDA approval, it must be as effective as drugs that are already approved.
However, 85% of respondents answered correctly that FDA-approved drugs typically have a favorable benefit/harm ratio.
Seventy percent of respondents incorrectly believed that FDA approval requires a drug to have both a statistically significant and a clinically important effect.
Only 6% of respondents knew the correct answer—that neither is required.
Breakthrough designation
Twenty percent of respondents said they were “familiar” (17%) or “very familiar” (3%) with breakthrough therapy designation, while 37% said they were “a little familiar,” and 42% said they were “not familiar at all.”
Fifty-eight percent of respondents said they were “fairly certain” that an FDA-approved breakthrough drug represents a major advance over currently approved treatments for its indication. Thirty-one percent said they were “fairly uncertain,” 5% said they were “very uncertain,” and 6% said they were “very certain.”
Fifty-two percent of respondents incorrectly believed that strong evidence (ie, randomized trials) is needed to earn the breakthrough designation.
However, 45% correctly answered that only preliminary evidence (eg, uncontrolled studies or studies testing surrogate outcomes) is needed. Four percent said very preliminary evidence (eg, in vitro laboratory or animal studies) is needed.
Seventy-seven percent of respondents incorrectly believed that, when the FDA grants breakthrough designation, there is high-quality evidence that the drug is more effective than currently approved treatments.
But 74% of respondents answered correctly that breakthrough designation does not mean there is high-quality evidence that the drug is safer than currently approved treatments.
Dr Kesselheim and his colleagues said the misconceptions identified in this survey may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to patients.