HT Staff

Lab mouse

Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.

The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.

One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.

The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.

The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.

Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).

The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.

The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.

The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.

The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.

Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.

The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.

The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.

“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”

Lab mouse

Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.

The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.

One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.

The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.

The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.

Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).

The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.

The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.

The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.

The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.

Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.

The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.

The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.

“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”

Lab mouse

Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.

The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.

One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.

The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.

The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.

Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).

The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.

The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.

The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.

The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.

Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.

The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.

The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.

“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”

Photo by Esther Dyson

MADRID—Results of a nationwide study suggest many cancer patients in Ireland don’t understand key aspects of clinical trial methodology.

Most of the patients surveyed, which included individuals who had participated in a clinical trial, did not understand the concepts of randomization or equipoise.

“Over half of previous medical trial participants and 73% of those who had never been on a cancer clinical trial did not understand that, in a randomized trial, the treatment given was decided by chance,” said study investigator Catherine Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, Ireland.

“We also found that most patients did not understand clinical equipoise—the fact that no one knows which treatment is best. Surprisingly, this was more marked in previous clinical trial participants, 60% of whom believed that their doctor would know which study arm was best.”

Dr Kelly and her colleagues presented these findings at the ESMO 2017 Congress (abstract 1465P_PR).

The researchers surveyed 1090 adult cancer patients treated at 1 of 14 participating oncology centers across Ireland.

The patients’ median age was 60 (range, 50-69), 64.4% were female, and 66% were diagnosed between 2014 and 2016. The most common cancer types were breast (31.4%), colorectal (15.6%), hematologic (12.6%), genitourinary (11.6%), and lung (6.8%).

The patients filled out anonymized questionnaires in which they were asked to evaluate statements about clinical trials. The patients had to determine whether a statement is true or false, or they could indicate that they didn’t know an answer.

A majority of the patients (82.3%) said they understood what a medical or cancer clinical trial is. And 27.8% of patients said they had previously participated in a cancer trial.

However, many patients didn’t know when clinical trials may be an option. Twenty-two percent of patients said it is true that “clinical trials are only used when standard treatments have not worked,” and 26.6% said they didn’t know if this statement is true or false.

Roughly a third (33.5%) of patients said it is true that, in a randomized trial, treatment is decided by chance, but 41.4% of patients said this is false, and 25% said they didn’t know.

More than half of patients (56.5%) said their doctor would know which treatment was superior in a clinical trial, and 23.2% of patients said they didn’t know if their doctor would know.

About 61% of all patients said their doctor would make sure they received the superior treatment in a clinical trial. An even greater percentage—63.6%—of patients who had previously participated in a clinical trial said the same.

“To provide informed consent when participating in a trial, patients need to understand these key concepts, and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating,” Dr Kelly said.

“Doctors have a responsibility to properly inform their patients in this regard because they are the ones patients trust the most. As we analyze the data further, we will be able to offer physicians a more detailed picture of the questions patients need answered and the factors that influence their decision-making according to age group, cancer type, educational background, and other demographics.”

Funding for this research was provided to Cancer Trials Ireland by Amgen, Abbvie, Bayor, and Inveva.

Photo by Esther Dyson

MADRID—Results of a nationwide study suggest many cancer patients in Ireland don’t understand key aspects of clinical trial methodology.

Most of the patients surveyed, which included individuals who had participated in a clinical trial, did not understand the concepts of randomization or equipoise.

“Over half of previous medical trial participants and 73% of those who had never been on a cancer clinical trial did not understand that, in a randomized trial, the treatment given was decided by chance,” said study investigator Catherine Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, Ireland.

“We also found that most patients did not understand clinical equipoise—the fact that no one knows which treatment is best. Surprisingly, this was more marked in previous clinical trial participants, 60% of whom believed that their doctor would know which study arm was best.”

Dr Kelly and her colleagues presented these findings at the ESMO 2017 Congress (abstract 1465P_PR).

The researchers surveyed 1090 adult cancer patients treated at 1 of 14 participating oncology centers across Ireland.

The patients’ median age was 60 (range, 50-69), 64.4% were female, and 66% were diagnosed between 2014 and 2016. The most common cancer types were breast (31.4%), colorectal (15.6%), hematologic (12.6%), genitourinary (11.6%), and lung (6.8%).

The patients filled out anonymized questionnaires in which they were asked to evaluate statements about clinical trials. The patients had to determine whether a statement is true or false, or they could indicate that they didn’t know an answer.

A majority of the patients (82.3%) said they understood what a medical or cancer clinical trial is. And 27.8% of patients said they had previously participated in a cancer trial.

However, many patients didn’t know when clinical trials may be an option. Twenty-two percent of patients said it is true that “clinical trials are only used when standard treatments have not worked,” and 26.6% said they didn’t know if this statement is true or false.

Roughly a third (33.5%) of patients said it is true that, in a randomized trial, treatment is decided by chance, but 41.4% of patients said this is false, and 25% said they didn’t know.

More than half of patients (56.5%) said their doctor would know which treatment was superior in a clinical trial, and 23.2% of patients said they didn’t know if their doctor would know.

About 61% of all patients said their doctor would make sure they received the superior treatment in a clinical trial. An even greater percentage—63.6%—of patients who had previously participated in a clinical trial said the same.

“To provide informed consent when participating in a trial, patients need to understand these key concepts, and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating,” Dr Kelly said.

“Doctors have a responsibility to properly inform their patients in this regard because they are the ones patients trust the most. As we analyze the data further, we will be able to offer physicians a more detailed picture of the questions patients need answered and the factors that influence their decision-making according to age group, cancer type, educational background, and other demographics.”

Funding for this research was provided to Cancer Trials Ireland by Amgen, Abbvie, Bayor, and Inveva.

Photo by Esther Dyson

MADRID—Results of a nationwide study suggest many cancer patients in Ireland don’t understand key aspects of clinical trial methodology.

Most of the patients surveyed, which included individuals who had participated in a clinical trial, did not understand the concepts of randomization or equipoise.

“Over half of previous medical trial participants and 73% of those who had never been on a cancer clinical trial did not understand that, in a randomized trial, the treatment given was decided by chance,” said study investigator Catherine Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, Ireland.

“We also found that most patients did not understand clinical equipoise—the fact that no one knows which treatment is best. Surprisingly, this was more marked in previous clinical trial participants, 60% of whom believed that their doctor would know which study arm was best.”

Dr Kelly and her colleagues presented these findings at the ESMO 2017 Congress (abstract 1465P_PR).

The researchers surveyed 1090 adult cancer patients treated at 1 of 14 participating oncology centers across Ireland.

The patients’ median age was 60 (range, 50-69), 64.4% were female, and 66% were diagnosed between 2014 and 2016. The most common cancer types were breast (31.4%), colorectal (15.6%), hematologic (12.6%), genitourinary (11.6%), and lung (6.8%).

The patients filled out anonymized questionnaires in which they were asked to evaluate statements about clinical trials. The patients had to determine whether a statement is true or false, or they could indicate that they didn’t know an answer.

A majority of the patients (82.3%) said they understood what a medical or cancer clinical trial is. And 27.8% of patients said they had previously participated in a cancer trial.

However, many patients didn’t know when clinical trials may be an option. Twenty-two percent of patients said it is true that “clinical trials are only used when standard treatments have not worked,” and 26.6% said they didn’t know if this statement is true or false.

Roughly a third (33.5%) of patients said it is true that, in a randomized trial, treatment is decided by chance, but 41.4% of patients said this is false, and 25% said they didn’t know.

More than half of patients (56.5%) said their doctor would know which treatment was superior in a clinical trial, and 23.2% of patients said they didn’t know if their doctor would know.

About 61% of all patients said their doctor would make sure they received the superior treatment in a clinical trial. An even greater percentage—63.6%—of patients who had previously participated in a clinical trial said the same.

“To provide informed consent when participating in a trial, patients need to understand these key concepts, and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating,” Dr Kelly said.

“Doctors have a responsibility to properly inform their patients in this regard because they are the ones patients trust the most. As we analyze the data further, we will be able to offer physicians a more detailed picture of the questions patients need answered and the factors that influence their decision-making according to age group, cancer type, educational background, and other demographics.”

Funding for this research was provided to Cancer Trials Ireland by Amgen, Abbvie, Bayor, and Inveva.

Red blood cells

Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).

The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.

The sequencing revealed a mutation in the gene CLPX that promotes EPP.

Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.

About EPP

To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.

In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.

“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”

Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.

New discovery

Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).

In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.

The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.

“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.

Red blood cells

Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).

The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.

The sequencing revealed a mutation in the gene CLPX that promotes EPP.

Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.

About EPP

To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.

In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.

“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”

Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.

New discovery

Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).

In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.

The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.

“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.

Red blood cells

Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).

The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.

The sequencing revealed a mutation in the gene CLPX that promotes EPP.

Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.

About EPP

To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.

In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.

“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”

Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.

New discovery

Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).

In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.

The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.

“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Image by Kevin MacKenzie

Taller individuals have an increased risk of venous thromboembolism (VTE), according to research published in Circulation: Cardiovascular Genetics.

In a study of more than 2 million Swedish siblings, researchers found that height was an independent predictor of VTE, with the lowest VTE risk observed in the shortest participants.

The association between height and VTE was present in both men and women (all of whom had been pregnant).

“Height is not something we can do anything about,” noted study author Bengt Zöller, MD, PhD, of Lund University and Malmö University Hospital in Sweden.

“However, the height in the population has increased and continues increasing, which could be contributing to the fact that the incidence of thrombosis has increased.”

For this study, Dr Zöller and his colleagues analyzed 2 cohorts of Swedish individuals without a prior VTE.

There were 1,610,870 men who were followed from enrollment—1969 to 2010—until 2012.

And there were 1,093,342 women who were followed from their first pregnancy—1982 to 2012—until 2012.

The researchers identified sibling pairs so they could adjust their analysis for genetic and environmental factors that might impact VTE risk.

The team found the risk of VTE was 69% lower for the shortest women (<155 cm, <5′1″) than it was for the tallest women (≥185 cm, ≥6′).

The risk of VTE was 65% lower for the shortest men (<160 cm, <5′3″) than the tallest men (≥190 cm, ≥6′2″).

Dr Zöller said gravity may influence the association between height and VTE risk.

“It could just be that because taller individuals have longer leg veins, there is more surface area where problems can occur,” he said. “There is also more gravitational pressure in leg veins of taller persons that can increase the risk of blood flow slowing or temporarily stopping.”

It is worth noting that the researchers didn’t have access to data for childhood and parent lifestyle factors that might influence VTE risk, such as smoking, diet, and physical activity. In addition, the study consisted of Swedish people and may not be translatable to other populations.

Nevertheless, Dr Zöller said, “I think we should start to include height in [VTE] risk assessment, just as [we do] overweight, although formal studies are needed to determine exactly how height interacts with inherited blood disorders and other conditions.”

Image by Kevin MacKenzie

Taller individuals have an increased risk of venous thromboembolism (VTE), according to research published in Circulation: Cardiovascular Genetics.

In a study of more than 2 million Swedish siblings, researchers found that height was an independent predictor of VTE, with the lowest VTE risk observed in the shortest participants.

The association between height and VTE was present in both men and women (all of whom had been pregnant).

“Height is not something we can do anything about,” noted study author Bengt Zöller, MD, PhD, of Lund University and Malmö University Hospital in Sweden.

“However, the height in the population has increased and continues increasing, which could be contributing to the fact that the incidence of thrombosis has increased.”

For this study, Dr Zöller and his colleagues analyzed 2 cohorts of Swedish individuals without a prior VTE.

There were 1,610,870 men who were followed from enrollment—1969 to 2010—until 2012.

And there were 1,093,342 women who were followed from their first pregnancy—1982 to 2012—until 2012.

The researchers identified sibling pairs so they could adjust their analysis for genetic and environmental factors that might impact VTE risk.

The team found the risk of VTE was 69% lower for the shortest women (<155 cm, <5′1″) than it was for the tallest women (≥185 cm, ≥6′).

The risk of VTE was 65% lower for the shortest men (<160 cm, <5′3″) than the tallest men (≥190 cm, ≥6′2″).

Dr Zöller said gravity may influence the association between height and VTE risk.

“It could just be that because taller individuals have longer leg veins, there is more surface area where problems can occur,” he said. “There is also more gravitational pressure in leg veins of taller persons that can increase the risk of blood flow slowing or temporarily stopping.”

It is worth noting that the researchers didn’t have access to data for childhood and parent lifestyle factors that might influence VTE risk, such as smoking, diet, and physical activity. In addition, the study consisted of Swedish people and may not be translatable to other populations.

Nevertheless, Dr Zöller said, “I think we should start to include height in [VTE] risk assessment, just as [we do] overweight, although formal studies are needed to determine exactly how height interacts with inherited blood disorders and other conditions.”

Image by Kevin MacKenzie

Taller individuals have an increased risk of venous thromboembolism (VTE), according to research published in Circulation: Cardiovascular Genetics.

In a study of more than 2 million Swedish siblings, researchers found that height was an independent predictor of VTE, with the lowest VTE risk observed in the shortest participants.

The association between height and VTE was present in both men and women (all of whom had been pregnant).

“Height is not something we can do anything about,” noted study author Bengt Zöller, MD, PhD, of Lund University and Malmö University Hospital in Sweden.

“However, the height in the population has increased and continues increasing, which could be contributing to the fact that the incidence of thrombosis has increased.”

For this study, Dr Zöller and his colleagues analyzed 2 cohorts of Swedish individuals without a prior VTE.

There were 1,610,870 men who were followed from enrollment—1969 to 2010—until 2012.

And there were 1,093,342 women who were followed from their first pregnancy—1982 to 2012—until 2012.

The researchers identified sibling pairs so they could adjust their analysis for genetic and environmental factors that might impact VTE risk.

The team found the risk of VTE was 69% lower for the shortest women (<155 cm, <5′1″) than it was for the tallest women (≥185 cm, ≥6′).

The risk of VTE was 65% lower for the shortest men (<160 cm, <5′3″) than the tallest men (≥190 cm, ≥6′2″).

Dr Zöller said gravity may influence the association between height and VTE risk.

“It could just be that because taller individuals have longer leg veins, there is more surface area where problems can occur,” he said. “There is also more gravitational pressure in leg veins of taller persons that can increase the risk of blood flow slowing or temporarily stopping.”

It is worth noting that the researchers didn’t have access to data for childhood and parent lifestyle factors that might influence VTE risk, such as smoking, diet, and physical activity. In addition, the study consisted of Swedish people and may not be translatable to other populations.

Nevertheless, Dr Zöller said, “I think we should start to include height in [VTE] risk assessment, just as [we do] overweight, although formal studies are needed to determine exactly how height interacts with inherited blood disorders and other conditions.”

College of Medicine

Researchers say they have discovered a novel role for heparin as a promoter of food intake and weight gain in animal models.

The team’s findings suggest heparin could be a potential target for drugs regulating appetite and weight control.

“In addition to its role as an anticoagulant, heparin, which is normally produced by the body, has been known to affect other biological functions,” said Yong Xu, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“In this study, we are among the first groups to investigate heparin’s potential role in regulating the body’s energy balance.”

Dr Xu and his colleagues described this study in Cell Reports.

“Our earlier studies showed that serum heparin levels in mice increased significantly during starvation,” said Dr Gang Shu, of South China Agricultural University in Guangzhou, China.

“These encouraged us to explore a potential role of heparin in feeding control.”

This exploration revealed that treatment with heparin increased food intake and body weight in male and female mice.

Then, the researchers found that heparin stimulates AgRP neurons located in the hypothalamus. This results in increased production of AgRP protein, a neuropeptide that stimulates food intake.

“We also demonstrated that heparin activates AgRP neurons by competing with insulin for binding to the insulin receptor,” Dr Shu said.

“Insulin and heparin have opposite effects on AgRP neurons,” Dr Xu noted. “Insulin treatment suppresses AgRP neuron firing of electrical impulses and expression of AgRP neuropeptides. We found that heparin competes with and prevents insulin from binding to insulin receptors on AgRP neurons.”

The researchers also found that, by competing for insulin receptor binding, heparin inhibits FoxO1 activity to promote AgRP release and feeding.

The team noted that FoxO1 has been shown to be highly expressed in AgRP neurons and to represent a key intracellular component of pathways integrating AgRP-mediated food intake and peripheral metabolic signals.

Although this study was conducted in animals, the researchers believe its results have implications for patients. The research suggests heparin can affect how the body regulates appetite, so heparin might be a target for treating eating disorders.

College of Medicine

Researchers say they have discovered a novel role for heparin as a promoter of food intake and weight gain in animal models.

The team’s findings suggest heparin could be a potential target for drugs regulating appetite and weight control.

“In addition to its role as an anticoagulant, heparin, which is normally produced by the body, has been known to affect other biological functions,” said Yong Xu, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“In this study, we are among the first groups to investigate heparin’s potential role in regulating the body’s energy balance.”

Dr Xu and his colleagues described this study in Cell Reports.

“Our earlier studies showed that serum heparin levels in mice increased significantly during starvation,” said Dr Gang Shu, of South China Agricultural University in Guangzhou, China.

“These encouraged us to explore a potential role of heparin in feeding control.”

This exploration revealed that treatment with heparin increased food intake and body weight in male and female mice.

Then, the researchers found that heparin stimulates AgRP neurons located in the hypothalamus. This results in increased production of AgRP protein, a neuropeptide that stimulates food intake.

“We also demonstrated that heparin activates AgRP neurons by competing with insulin for binding to the insulin receptor,” Dr Shu said.

“Insulin and heparin have opposite effects on AgRP neurons,” Dr Xu noted. “Insulin treatment suppresses AgRP neuron firing of electrical impulses and expression of AgRP neuropeptides. We found that heparin competes with and prevents insulin from binding to insulin receptors on AgRP neurons.”

The researchers also found that, by competing for insulin receptor binding, heparin inhibits FoxO1 activity to promote AgRP release and feeding.

The team noted that FoxO1 has been shown to be highly expressed in AgRP neurons and to represent a key intracellular component of pathways integrating AgRP-mediated food intake and peripheral metabolic signals.

Although this study was conducted in animals, the researchers believe its results have implications for patients. The research suggests heparin can affect how the body regulates appetite, so heparin might be a target for treating eating disorders.

College of Medicine

Researchers say they have discovered a novel role for heparin as a promoter of food intake and weight gain in animal models.

The team’s findings suggest heparin could be a potential target for drugs regulating appetite and weight control.

“In addition to its role as an anticoagulant, heparin, which is normally produced by the body, has been known to affect other biological functions,” said Yong Xu, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“In this study, we are among the first groups to investigate heparin’s potential role in regulating the body’s energy balance.”

Dr Xu and his colleagues described this study in Cell Reports.

“Our earlier studies showed that serum heparin levels in mice increased significantly during starvation,” said Dr Gang Shu, of South China Agricultural University in Guangzhou, China.

“These encouraged us to explore a potential role of heparin in feeding control.”

This exploration revealed that treatment with heparin increased food intake and body weight in male and female mice.

Then, the researchers found that heparin stimulates AgRP neurons located in the hypothalamus. This results in increased production of AgRP protein, a neuropeptide that stimulates food intake.

“We also demonstrated that heparin activates AgRP neurons by competing with insulin for binding to the insulin receptor,” Dr Shu said.

“Insulin and heparin have opposite effects on AgRP neurons,” Dr Xu noted. “Insulin treatment suppresses AgRP neuron firing of electrical impulses and expression of AgRP neuropeptides. We found that heparin competes with and prevents insulin from binding to insulin receptors on AgRP neurons.”

The researchers also found that, by competing for insulin receptor binding, heparin inhibits FoxO1 activity to promote AgRP release and feeding.

The team noted that FoxO1 has been shown to be highly expressed in AgRP neurons and to represent a key intracellular component of pathways integrating AgRP-mediated food intake and peripheral metabolic signals.

Although this study was conducted in animals, the researchers believe its results have implications for patients. The research suggests heparin can affect how the body regulates appetite, so heparin might be a target for treating eating disorders.

Red blood cells

Physicians have long known that patients with an underactive thyroid tend to have anemia because thyroid hormone stimulates red blood cell (RBC) production.

Now, researchers say they have determined how this occurs.

Xiaofei Gao, PhD, of Westlake Institute for Advanced Study in Hangzhou, Zhejiang Province, China, and his colleagues conducted this research and reported the results in PNAS.

The team began by studying the formation of human RBCs in culture. They wondered if something in the culture serum was essential for RBC maturation. So they ran the serum through a charcoal filter, which attracts and retains hydrophobic molecules.

Once filtered, the serum no longer supported RBC production. This validated the researchers’ theory that one of the hydrophobic molecules was key to RBC maturation.

In fact, the team found thyroid hormone was essential for the final step of RBC maturation.

When the researchers added thyroid hormone back to the serum, RBC progenitors once again started down the path to maturation.

If thyroid hormone was added at an earlier stage of development, the RBCs short-circuited their usual developmental processes and began turning into mature RBCs.

With further investigation, the researchers pinpointed the receptor inside maturing RBCs to which thyroid hormone binds—thyroid hormone receptor beta (TRβ).

From there, the team found that nuclear receptor coactivator 4 (NCOA4), a protein necessary for thyroid hormone stimulation, works with TRβ to regulate RBC development.

Finally, experiments showed that TRβ agonists could stimulate RBC development and alleviate anemic symptoms in a mouse model of chronic anemia.

The researchers therefore believe this work could lead to new therapies for anemic patients, including those with an underactive thyroid.

Red blood cells

Physicians have long known that patients with an underactive thyroid tend to have anemia because thyroid hormone stimulates red blood cell (RBC) production.

Now, researchers say they have determined how this occurs.

Xiaofei Gao, PhD, of Westlake Institute for Advanced Study in Hangzhou, Zhejiang Province, China, and his colleagues conducted this research and reported the results in PNAS.

The team began by studying the formation of human RBCs in culture. They wondered if something in the culture serum was essential for RBC maturation. So they ran the serum through a charcoal filter, which attracts and retains hydrophobic molecules.

Once filtered, the serum no longer supported RBC production. This validated the researchers’ theory that one of the hydrophobic molecules was key to RBC maturation.

In fact, the team found thyroid hormone was essential for the final step of RBC maturation.

When the researchers added thyroid hormone back to the serum, RBC progenitors once again started down the path to maturation.

If thyroid hormone was added at an earlier stage of development, the RBCs short-circuited their usual developmental processes and began turning into mature RBCs.

With further investigation, the researchers pinpointed the receptor inside maturing RBCs to which thyroid hormone binds—thyroid hormone receptor beta (TRβ).

From there, the team found that nuclear receptor coactivator 4 (NCOA4), a protein necessary for thyroid hormone stimulation, works with TRβ to regulate RBC development.

Finally, experiments showed that TRβ agonists could stimulate RBC development and alleviate anemic symptoms in a mouse model of chronic anemia.

The researchers therefore believe this work could lead to new therapies for anemic patients, including those with an underactive thyroid.

Red blood cells

Physicians have long known that patients with an underactive thyroid tend to have anemia because thyroid hormone stimulates red blood cell (RBC) production.

Now, researchers say they have determined how this occurs.

Xiaofei Gao, PhD, of Westlake Institute for Advanced Study in Hangzhou, Zhejiang Province, China, and his colleagues conducted this research and reported the results in PNAS.

The team began by studying the formation of human RBCs in culture. They wondered if something in the culture serum was essential for RBC maturation. So they ran the serum through a charcoal filter, which attracts and retains hydrophobic molecules.

Once filtered, the serum no longer supported RBC production. This validated the researchers’ theory that one of the hydrophobic molecules was key to RBC maturation.

In fact, the team found thyroid hormone was essential for the final step of RBC maturation.

When the researchers added thyroid hormone back to the serum, RBC progenitors once again started down the path to maturation.

If thyroid hormone was added at an earlier stage of development, the RBCs short-circuited their usual developmental processes and began turning into mature RBCs.

With further investigation, the researchers pinpointed the receptor inside maturing RBCs to which thyroid hormone binds—thyroid hormone receptor beta (TRβ).

From there, the team found that nuclear receptor coactivator 4 (NCOA4), a protein necessary for thyroid hormone stimulation, works with TRβ to regulate RBC development.

Finally, experiments showed that TRβ agonists could stimulate RBC development and alleviate anemic symptoms in a mouse model of chronic anemia.

The researchers therefore believe this work could lead to new therapies for anemic patients, including those with an underactive thyroid.