HT Staff

Doctor and patient in hospital

Photo courtesy of CDC

A retrospective study has uncovered potential risk factors for early death in older patients with diffuse large B-cell lymphoma (DLBCL).

Researchers examined electronic health record data for roughly 5500 DLBCL patients over the age of 65 who received contemporary immunochemotherapy.

This revealed 7 factors that were significantly associated with the risk of death within 30 days of treatment initiation.

“The first month of treatment, when patients are compromised both by active lymphoma and toxicities of chemotherapy, is a period of particular concern, as nearly 1 in 4 patients were hospitalized during that time,” said study author Adam J. Olszewski, MD, of Rhode Island Hospital in Providence.

“While comprehensive geriatric assessment remains the gold standard for risk assessment, our study suggests that readily available data from electronic medical records can help identify the high-risk factors in practice.”

Dr Olszewski and his colleagues described their study in JNCCN.

The researchers looked at Medicare claims linked to Surveillance, Epidemiology and End Results registry data for 5530 DLBCL patients who had a median age of 76.

The patients were treated with rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide from 2003 to 2012.

The cumulative incidence of death at 30 days was 2.2%. The most common causes of death were lymphoma (72%), heart disease (9%), septicemia (3%), and cerebrovascular events (3%).

The researchers created a prediction model based on 7 factors that were significantly associated with early death in multivariate analysis. These include:

• B symptoms
• Chronic kidney disease
• Poor performance status
• Prior use of walking aids or wheelchairs
• Prior hospitalization within the past 12 months
• Upper endoscopy within the past 12 months
• Age 75 or older.

Patients with 0 to 1 of these risk factors were considered low-risk, with a 0.6% chance of early death. Fifty-six percent of the patients studied fit this definition.

Patients with 2 to 3 of the risk factors were intermediate-risk, with a 3.2% chance of early death. Thirty-eight percent of the patients studied fell into this category.

Only 6% of the patients studied were considered high-risk. These patients had 4 or more risk factors and an 8.3% chance of early death.

The researchers also found the administration of prophylactic granulocyte-colony stimulating factor (G-CSF) was associated with lower probability of early death in the high-risk group.

They noted that prophylactic G-CSF was given to 66% of patients in this study, which suggests an opportunity for preventing early deaths.

“It is equally important to realize that a majority of older patients without risk factors can safely receive curative immunochemotherapy,” Dr Olszewski said. “Enhanced supportive care and monitoring should be provided for high-risk groups.”

Doctor and patient in hospital

Photo courtesy of CDC

A retrospective study has uncovered potential risk factors for early death in older patients with diffuse large B-cell lymphoma (DLBCL).

Researchers examined electronic health record data for roughly 5500 DLBCL patients over the age of 65 who received contemporary immunochemotherapy.

This revealed 7 factors that were significantly associated with the risk of death within 30 days of treatment initiation.

“The first month of treatment, when patients are compromised both by active lymphoma and toxicities of chemotherapy, is a period of particular concern, as nearly 1 in 4 patients were hospitalized during that time,” said study author Adam J. Olszewski, MD, of Rhode Island Hospital in Providence.

“While comprehensive geriatric assessment remains the gold standard for risk assessment, our study suggests that readily available data from electronic medical records can help identify the high-risk factors in practice.”

Dr Olszewski and his colleagues described their study in JNCCN.

The researchers looked at Medicare claims linked to Surveillance, Epidemiology and End Results registry data for 5530 DLBCL patients who had a median age of 76.

The patients were treated with rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide from 2003 to 2012.

The cumulative incidence of death at 30 days was 2.2%. The most common causes of death were lymphoma (72%), heart disease (9%), septicemia (3%), and cerebrovascular events (3%).

The researchers created a prediction model based on 7 factors that were significantly associated with early death in multivariate analysis. These include:

• B symptoms
• Chronic kidney disease
• Poor performance status
• Prior use of walking aids or wheelchairs
• Prior hospitalization within the past 12 months
• Upper endoscopy within the past 12 months
• Age 75 or older.

Patients with 0 to 1 of these risk factors were considered low-risk, with a 0.6% chance of early death. Fifty-six percent of the patients studied fit this definition.

Patients with 2 to 3 of the risk factors were intermediate-risk, with a 3.2% chance of early death. Thirty-eight percent of the patients studied fell into this category.

Only 6% of the patients studied were considered high-risk. These patients had 4 or more risk factors and an 8.3% chance of early death.

The researchers also found the administration of prophylactic granulocyte-colony stimulating factor (G-CSF) was associated with lower probability of early death in the high-risk group.

They noted that prophylactic G-CSF was given to 66% of patients in this study, which suggests an opportunity for preventing early deaths.

“It is equally important to realize that a majority of older patients without risk factors can safely receive curative immunochemotherapy,” Dr Olszewski said. “Enhanced supportive care and monitoring should be provided for high-risk groups.”

Doctor and patient in hospital

Photo courtesy of CDC

A retrospective study has uncovered potential risk factors for early death in older patients with diffuse large B-cell lymphoma (DLBCL).

Researchers examined electronic health record data for roughly 5500 DLBCL patients over the age of 65 who received contemporary immunochemotherapy.

This revealed 7 factors that were significantly associated with the risk of death within 30 days of treatment initiation.

“The first month of treatment, when patients are compromised both by active lymphoma and toxicities of chemotherapy, is a period of particular concern, as nearly 1 in 4 patients were hospitalized during that time,” said study author Adam J. Olszewski, MD, of Rhode Island Hospital in Providence.

“While comprehensive geriatric assessment remains the gold standard for risk assessment, our study suggests that readily available data from electronic medical records can help identify the high-risk factors in practice.”

Dr Olszewski and his colleagues described their study in JNCCN.

The researchers looked at Medicare claims linked to Surveillance, Epidemiology and End Results registry data for 5530 DLBCL patients who had a median age of 76.

The patients were treated with rituximab, cyclophosphamide, and vincristine in combination with doxorubicin, mitoxantrone, or etoposide from 2003 to 2012.

The cumulative incidence of death at 30 days was 2.2%. The most common causes of death were lymphoma (72%), heart disease (9%), septicemia (3%), and cerebrovascular events (3%).

The researchers created a prediction model based on 7 factors that were significantly associated with early death in multivariate analysis. These include:

• B symptoms
• Chronic kidney disease
• Poor performance status
• Prior use of walking aids or wheelchairs
• Prior hospitalization within the past 12 months
• Upper endoscopy within the past 12 months
• Age 75 or older.

Patients with 0 to 1 of these risk factors were considered low-risk, with a 0.6% chance of early death. Fifty-six percent of the patients studied fit this definition.

Patients with 2 to 3 of the risk factors were intermediate-risk, with a 3.2% chance of early death. Thirty-eight percent of the patients studied fell into this category.

Only 6% of the patients studied were considered high-risk. These patients had 4 or more risk factors and an 8.3% chance of early death.

The researchers also found the administration of prophylactic granulocyte-colony stimulating factor (G-CSF) was associated with lower probability of early death in the high-risk group.

They noted that prophylactic G-CSF was given to 66% of patients in this study, which suggests an opportunity for preventing early deaths.

“It is equally important to realize that a majority of older patients without risk factors can safely receive curative immunochemotherapy,” Dr Olszewski said. “Enhanced supportive care and monitoring should be provided for high-risk groups.”

Sickled and normal red

blood cells from a mouse

Image courtesy of

University of Michigan

Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).

The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.

Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.

The team reported these findings in The Journal of Clinical Investigation.

Previous research showed that suppressing BCL11A can replace the defective beta

hemoglobin that causes sickling with healthy fetal hemoglobin.

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.

“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).

To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.

Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.

To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.

HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.

When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers

of reticulocytes.

Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.

Sickled and normal red

blood cells from a mouse

Image courtesy of

University of Michigan

Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).

The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.

Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.

The team reported these findings in The Journal of Clinical Investigation.

Previous research showed that suppressing BCL11A can replace the defective beta

hemoglobin that causes sickling with healthy fetal hemoglobin.

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.

“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).

To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.

Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.

To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.

HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.

When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers

of reticulocytes.

Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.

Sickled and normal red

blood cells from a mouse

Image courtesy of

University of Michigan

Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).

The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.

Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.

The team reported these findings in The Journal of Clinical Investigation.

Previous research showed that suppressing BCL11A can replace the defective beta

hemoglobin that causes sickling with healthy fetal hemoglobin.

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.

“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).

To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.

Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.

To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.

HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.

When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers

of reticulocytes.

Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

 

 

Stanley Riddell, MD

Photo from Fred Hutchinson

Cancer Research Center

 

Results from a phase 1 study have provided insights that may help researchers optimize treatment with JCAR014, a chimeric antigen receptor (CAR) T-cell therapy, in patients with advanced non-Hodgkin lymphoma (NHL).

Researchers said they identified a lymphodepleting regimen that improved the likelihood of complete response (CR) to JCAR014.

Although the regimen also increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, the researchers discovered biomarkers that might allow them to identify patients who have a high risk of these events and could potentially benefit from early interventions.

The researchers reported these findings in Science Translational Medicine. The trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing JCAR014.

Previous results from this trial, in patients with acute lymphoblastic leukemia, were published in The Journal of Clinical Investigation.

About JCAR014

JCAR014 is a CD19-directed CAR T-cell therapy in which CD4+ and CD8+ cells are administered in equal proportions.

“The idea . . . is that by [controlling the ratio of T cells], we would get more reproducible data around the effects of the cells—both beneficial effects against the cancer and also any side effects they might cause the patient,” said study author Stanley Riddell, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“And then, by adjusting the dose, we could improve what we call the therapeutic index—the benefit against the tumor—without too much toxicity.”

Patients and treatment

Dr Riddell and his colleagues reported results with JCAR014, following lymphodepleting chemotherapy, in 32 patients with NHL who had a median age of 58 (range, 36-70).

The patients had de novo large B-cell lymphoma (n=11), transformed de novo large B-cell lymphoma (n=11), mantle cell lymphoma (n=4), and follicular lymphoma (n=6).

They had received a median of 5 prior treatment regimens (range, 2 to 11), including autologous

(n=14) and allogeneic (n=4) transplant. All patients had measurable disease (≥ 2 cm) in the lymph nodes or other extramedullary sites at baseline.

The patients received JCAR014 at 1 of 3 dose levels, given 36 to 96 hours after lymphodepleting chemotherapy.

Twelve patients received cyclophosphamide (Cy) alone or Cy and etoposide (E), and 20 received Cy plus fludarabine (Flu). Five patients received 2 × 10⁵ CAR T cells/kg, 18 received 2 × 10⁶ CAR T cells/kg, and 9 received 2 × 10⁷ CAR T cells/kg.

Efficacy

In the 30 evaluable patients, the overall response rate (ORR) was 63% (n=19), and the CR rate was 33% (n=10).

Among patients who received Cy or Cy/E, the ORR was 50% (n=6), and the CR rate was 8% (n=1). Among patients who received Cy/Flu, the ORR was 72% (n=13), and the CR rate was 50% (n=9).

The patients who received Cy/Flu had better CAR T-cell expansion and persistence than patients who received Cy or Cy/E, which was reflected in the higher response rates.

Higher response rates were also observed in patients who received 2 × 10⁶ CAR T cells/kg rather than the other 2 dose levels.

The researchers noted that, although follow-up is short, patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy/Flu had better progression-free survival (P=0.008) than patients who received CAR T cells at ≤ 2 × 10⁶/kg after Cy or Cy/E.

Of the 9 patients who achieved a CR after Cy/Flu and JCAR014, 1 has relapsed, with follow-up ranging from 2.3 months to 11.2 months. (Seven of these 9 patients had received 2 × 10⁶ CAR T cells/kg, and 1 patient each had received the other 2 doses.)

“The main message is that you can treat patients with non-Hodgkin’s lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center.

“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome.”

Safety

Two patients who were treated with the highest CAR T-cell dose (2 × 10⁷ cells/kg) died—1 of pontine hemorrhage and 1 of gastrointestinal hemorrhage associated with a known gastrointestinal invasive lymphomatous mass.

This dose was also associated with an increased risk of severe CRS and neurotoxicity, as was the Cy/Flu regimen.

Twenty patients (62.5%) developed CRS, and 4 (12.5%) had severe CRS. All 4 of these patients had received Cy/Flu.

Nine patients (28%) developed severe neurotoxicity (grade 3 or higher), 7 of whom had received Cy/Flu.

Three of the 6 patients (50%) treated at 2 × 10⁷ CAR-T cells/kg after Cy/Flu developed severe CRS, and 4 of the 6 patients (67%) developed severe neurotoxicity.

The researchers looked for biomarkers of toxicity in serum collected 1 day after CAR T-cell infusion.

They found that high IL-6, IL-8, IL-10, IL-15, and IFN-γ concentrations were associated with subsequent severe CRS and neurotoxicity, and low TGF-Β concentration was associated with neurotoxicity.

The team said these findings provide an opportunity for studying the use of serum cytokine concentrations to identify patients at the highest risk of toxicity who might benefit from early interventions.

A hand spraying a mist

of nasal spray

Bevacizumab nasal spray is no more effective than a placebo for reducing epistaxis caused by hereditary hemorrhagic telangiectasia (HHT), according to a study published in JAMA.

Researchers compared 3 different doses of bevacizumab to a sodium chloride placebo and found no significant difference between the treatment groups in the frequency or duration of epistaxis, the need for transfusion, or hemoglobin/ferritin levels.

Sophie Dupuis-Girod, MD, PhD, of the Hopital Femme-Mere-Enfants in Bron, France, and her colleagues conducted this trial, enrolling 80 patients with HHT and a history of epistaxis.

The patients were randomized to receive placebo (0.9% sodium chloride, n=21) or 1 of 3 doses of bevacizumab nasal spray.

Patients in the bevacizumab groups received 25 mg (n=20), 50 mg (n=20), or 75 mg (n=19) in 3 doses, 14 days apart, for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, or 225 mg.

Epistaxis duration

The researchers measured the mean monthly epistaxis duration at 3 months and found no significant difference between the placebo group and the bevacizumab groups (P=0.57). Likewise, there were no significant differences between the bevacizumab groups.

However, most of the groups experienced improvements in epistaxis duration after treatment.

The mean monthly epistaxis duration (in minutes) before treatment (from day −90 to day −1) and after treatment (from day 29 to day 118), respectively, was:

• 262.8 and 200.4 in the placebo group
• 285.5 and 259.2 in the 25 mg group
• 229.0 and 244.0 in the 50 mg group
• 272.9 and 215.0 in the 75 mg group.

Epistaxis frequency

There was no significant difference between the bevacizumab groups and the placebo group when it came to the number of epistaxis episodes (P=0.55). However, patients in all of the groups saw a reduction in episodes after treatment.

The mean number of epistaxis episodes before treatment (from day −90 to day −1) and after (from day 29 to day 118), respectively, were:

• 31.37 and 24.27 in the placebo group
• 30.99 and 23.13 in the 25 mg bevacizumab group
• 25.06 and 20.01 in the 50 mg bevacizumab group
• 27.84 and 24.35 in the 75 mg bevacizumab group.

Other outcomes

There was no significant difference between the bevacizumab groups and the placebo group regarding the number of red blood cell transfusions at 3 months (P=0.35) and 6 months (P=0.39), mean hemoglobin levels (P=0.66), and mean ferritin levels (P=0.86).

There were no adverse events (AEs) thought to be treatment-related. There were 161 AEs overall and no significant differences between the groups—47 AEs in the 25 mg bevacizumab group, 33 in the 50 mg bevacizumab group, 38 in the 75 mg bevacizumab group, and 43 in the placebo group.

After an interim analysis, an independent data monitoring committee recommended terminating this study early due to treatment futility. So the study was stopped before entering phase 3.

A hand spraying a mist

of nasal spray

Bevacizumab nasal spray is no more effective than a placebo for reducing epistaxis caused by hereditary hemorrhagic telangiectasia (HHT), according to a study published in JAMA.

Researchers compared 3 different doses of bevacizumab to a sodium chloride placebo and found no significant difference between the treatment groups in the frequency or duration of epistaxis, the need for transfusion, or hemoglobin/ferritin levels.

Sophie Dupuis-Girod, MD, PhD, of the Hopital Femme-Mere-Enfants in Bron, France, and her colleagues conducted this trial, enrolling 80 patients with HHT and a history of epistaxis.

The patients were randomized to receive placebo (0.9% sodium chloride, n=21) or 1 of 3 doses of bevacizumab nasal spray.

Patients in the bevacizumab groups received 25 mg (n=20), 50 mg (n=20), or 75 mg (n=19) in 3 doses, 14 days apart, for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, or 225 mg.

Epistaxis duration

The researchers measured the mean monthly epistaxis duration at 3 months and found no significant difference between the placebo group and the bevacizumab groups (P=0.57). Likewise, there were no significant differences between the bevacizumab groups.

However, most of the groups experienced improvements in epistaxis duration after treatment.

The mean monthly epistaxis duration (in minutes) before treatment (from day −90 to day −1) and after treatment (from day 29 to day 118), respectively, was:

• 262.8 and 200.4 in the placebo group
• 285.5 and 259.2 in the 25 mg group
• 229.0 and 244.0 in the 50 mg group
• 272.9 and 215.0 in the 75 mg group.

Epistaxis frequency

There was no significant difference between the bevacizumab groups and the placebo group when it came to the number of epistaxis episodes (P=0.55). However, patients in all of the groups saw a reduction in episodes after treatment.

The mean number of epistaxis episodes before treatment (from day −90 to day −1) and after (from day 29 to day 118), respectively, were:

• 31.37 and 24.27 in the placebo group
• 30.99 and 23.13 in the 25 mg bevacizumab group
• 25.06 and 20.01 in the 50 mg bevacizumab group
• 27.84 and 24.35 in the 75 mg bevacizumab group.

Other outcomes

There was no significant difference between the bevacizumab groups and the placebo group regarding the number of red blood cell transfusions at 3 months (P=0.35) and 6 months (P=0.39), mean hemoglobin levels (P=0.66), and mean ferritin levels (P=0.86).

There were no adverse events (AEs) thought to be treatment-related. There were 161 AEs overall and no significant differences between the groups—47 AEs in the 25 mg bevacizumab group, 33 in the 50 mg bevacizumab group, 38 in the 75 mg bevacizumab group, and 43 in the placebo group.

After an interim analysis, an independent data monitoring committee recommended terminating this study early due to treatment futility. So the study was stopped before entering phase 3.

A hand spraying a mist

of nasal spray

Bevacizumab nasal spray is no more effective than a placebo for reducing epistaxis caused by hereditary hemorrhagic telangiectasia (HHT), according to a study published in JAMA.

Researchers compared 3 different doses of bevacizumab to a sodium chloride placebo and found no significant difference between the treatment groups in the frequency or duration of epistaxis, the need for transfusion, or hemoglobin/ferritin levels.

Sophie Dupuis-Girod, MD, PhD, of the Hopital Femme-Mere-Enfants in Bron, France, and her colleagues conducted this trial, enrolling 80 patients with HHT and a history of epistaxis.

The patients were randomized to receive placebo (0.9% sodium chloride, n=21) or 1 of 3 doses of bevacizumab nasal spray.

Patients in the bevacizumab groups received 25 mg (n=20), 50 mg (n=20), or 75 mg (n=19) in 3 doses, 14 days apart, for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, or 225 mg.

Epistaxis duration

The researchers measured the mean monthly epistaxis duration at 3 months and found no significant difference between the placebo group and the bevacizumab groups (P=0.57). Likewise, there were no significant differences between the bevacizumab groups.

However, most of the groups experienced improvements in epistaxis duration after treatment.

The mean monthly epistaxis duration (in minutes) before treatment (from day −90 to day −1) and after treatment (from day 29 to day 118), respectively, was:

• 262.8 and 200.4 in the placebo group
• 285.5 and 259.2 in the 25 mg group
• 229.0 and 244.0 in the 50 mg group
• 272.9 and 215.0 in the 75 mg group.

Epistaxis frequency

There was no significant difference between the bevacizumab groups and the placebo group when it came to the number of epistaxis episodes (P=0.55). However, patients in all of the groups saw a reduction in episodes after treatment.

The mean number of epistaxis episodes before treatment (from day −90 to day −1) and after (from day 29 to day 118), respectively, were:

• 31.37 and 24.27 in the placebo group
• 30.99 and 23.13 in the 25 mg bevacizumab group
• 25.06 and 20.01 in the 50 mg bevacizumab group
• 27.84 and 24.35 in the 75 mg bevacizumab group.

Other outcomes

There was no significant difference between the bevacizumab groups and the placebo group regarding the number of red blood cell transfusions at 3 months (P=0.35) and 6 months (P=0.39), mean hemoglobin levels (P=0.66), and mean ferritin levels (P=0.86).

There were no adverse events (AEs) thought to be treatment-related. There were 161 AEs overall and no significant differences between the groups—47 AEs in the 25 mg bevacizumab group, 33 in the 50 mg bevacizumab group, 38 in the 75 mg bevacizumab group, and 43 in the placebo group.

After an interim analysis, an independent data monitoring committee recommended terminating this study early due to treatment futility. So the study was stopped before entering phase 3.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Hospital

A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.

The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.

The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.

The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.

Access to care

The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.

One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.

“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

Training and education

The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.

Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.

“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”

Research and clinical trials

The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.

The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.

Global issues

According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.

Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.

Sickle Cell Disease Coalition

To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.

The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.

The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Hospital

A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.

The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.

The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.

The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.

Access to care

The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.

One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.

“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

Training and education

The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.

Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.

“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”

Research and clinical trials

The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.

The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.

Global issues

According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.

Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.

Sickle Cell Disease Coalition

To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.

The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.

The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Hospital

A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.

The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.

The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.

The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.

Access to care

The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.

One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.

“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

Training and education

The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.

Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.

“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”

Research and clinical trials

The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.

The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.

Global issues

According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.

Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.

Sickle Cell Disease Coalition

To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.

The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.

The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.

Kevin Whitehead, MD

Photo courtesy of the

University of Utah

Health Sciences Center

Results of a phase 2 study suggest a saline nose spray may be as effective as 3 different medicated sprays for preventing epistaxis in patients with hemorrhagic telangiectasia (HHT).

The study was a comparison of bevacizumab, estriol, tranexamic acid, and saline.

The results showed no significant differences in the frequency or duration of epistaxis, and patients in all 4 groups reported improvements in Epistaxis Severity Scores (ESS).

“This research highlights that there could be a benefit even in the simplest of interventions,” said study author Kevin Whitehead, MD, of the University of Utah School of Medicine in Salt Lake City.

“No drug proved to be any better than the saline placebo, but the majority of patients improved over the course of treatment—even those using saline.”

Dr Whitehead and his colleagues reported these results in JAMA.

The study included 121 HHT patients who had experienced HHT-related epistaxis. They were randomized to twice-daily nose sprays with bevacizumab 1% (4 mg/day), estriol 0.1% (0.4 mg/day), tranexamic acid 10% (40 mg/day), or placebo (0.9% saline) for 12 weeks.

Safety

The investigators said nasal symptoms were the most common adverse events, and they occurred in all 4 treatment groups.

Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting, were most common among patients receiving tranexamic acid.

There were no thrombotic complications, episodes of severe hypertension, serious drug-related adverse events, or deaths in any treatment group.

Efficacy

There was no significant difference in epistaxis frequency between the placebo group and the other treatment groups (P=0.97).

After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 for patients in the bevacizumab group, 8.0 for the estriol group, 7.5 for the tranexamic acid group, and 8.0 for the placebo group. At baseline, the median weekly number of bleeding episodes was 10.0, 7.0, 7.8, and 7.0, respectively.

After 12 weeks of treatment, there was no significant difference in epistaxis duration between the placebo group and the other treatment groups (P=0.09).

The median duration of epistaxis per bleeding episode was 3.0 minutes for the bevacizumab group, 4.0 minutes for the estriol group, 6.2 minutes for the tranexamic acid group, and 5.0 minutes for the placebo group. (Bleeding duration was not recorded at baseline.)

After 12 weeks of treatment, there were no significant differences between the treatment groups when it came to hemoglobin levels (P=0.43), ferritin levels (P=0.10), treatment failure (P=0.08), the need for transfusion (P=0.42), or emergency department visits (P=0.72).

Patients in all 4 treatment groups experienced a significant decline in ESS from baseline to week 12 (P<0.001 for time effect).

The median ESS decreased from 5.71 to 3.74 in the placebo group, 5.16 to 3.54 in the bevacizumab group, 5.19 to 3.56 in the estriol group, and 5.43 to 4.06 in the tranexamic acid group. The investigators said the improvement in ESS was clinically significant.

However, the team also said they cannot completely rule out the possibility that symptoms may have improved because of a placebo effect.

What’s more, it could be that some of the drugs tested would work better if taken at a higher dose, or if applied as a gel or polymer that adheres better to the inside of the nasal cavity.

Nevertheless, the results from this trial were enough to convince Dr Whitehead and his colleagues to routinely recommend saline nasal spray to their patients with HHT.

“We stress the importance of hydration,” Dr Whitehead said. “We tell them that something as simple as a morning and night saline spray could offer them some benefit.”

Kevin Whitehead, MD

Photo courtesy of the

University of Utah

Health Sciences Center

Results of a phase 2 study suggest a saline nose spray may be as effective as 3 different medicated sprays for preventing epistaxis in patients with hemorrhagic telangiectasia (HHT).

The study was a comparison of bevacizumab, estriol, tranexamic acid, and saline.

The results showed no significant differences in the frequency or duration of epistaxis, and patients in all 4 groups reported improvements in Epistaxis Severity Scores (ESS).

“This research highlights that there could be a benefit even in the simplest of interventions,” said study author Kevin Whitehead, MD, of the University of Utah School of Medicine in Salt Lake City.

“No drug proved to be any better than the saline placebo, but the majority of patients improved over the course of treatment—even those using saline.”

Dr Whitehead and his colleagues reported these results in JAMA.

The study included 121 HHT patients who had experienced HHT-related epistaxis. They were randomized to twice-daily nose sprays with bevacizumab 1% (4 mg/day), estriol 0.1% (0.4 mg/day), tranexamic acid 10% (40 mg/day), or placebo (0.9% saline) for 12 weeks.

Safety

The investigators said nasal symptoms were the most common adverse events, and they occurred in all 4 treatment groups.

Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting, were most common among patients receiving tranexamic acid.

There were no thrombotic complications, episodes of severe hypertension, serious drug-related adverse events, or deaths in any treatment group.

Efficacy

There was no significant difference in epistaxis frequency between the placebo group and the other treatment groups (P=0.97).

After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 for patients in the bevacizumab group, 8.0 for the estriol group, 7.5 for the tranexamic acid group, and 8.0 for the placebo group. At baseline, the median weekly number of bleeding episodes was 10.0, 7.0, 7.8, and 7.0, respectively.

After 12 weeks of treatment, there was no significant difference in epistaxis duration between the placebo group and the other treatment groups (P=0.09).

The median duration of epistaxis per bleeding episode was 3.0 minutes for the bevacizumab group, 4.0 minutes for the estriol group, 6.2 minutes for the tranexamic acid group, and 5.0 minutes for the placebo group. (Bleeding duration was not recorded at baseline.)

After 12 weeks of treatment, there were no significant differences between the treatment groups when it came to hemoglobin levels (P=0.43), ferritin levels (P=0.10), treatment failure (P=0.08), the need for transfusion (P=0.42), or emergency department visits (P=0.72).

Patients in all 4 treatment groups experienced a significant decline in ESS from baseline to week 12 (P<0.001 for time effect).

The median ESS decreased from 5.71 to 3.74 in the placebo group, 5.16 to 3.54 in the bevacizumab group, 5.19 to 3.56 in the estriol group, and 5.43 to 4.06 in the tranexamic acid group. The investigators said the improvement in ESS was clinically significant.

However, the team also said they cannot completely rule out the possibility that symptoms may have improved because of a placebo effect.

What’s more, it could be that some of the drugs tested would work better if taken at a higher dose, or if applied as a gel or polymer that adheres better to the inside of the nasal cavity.

Nevertheless, the results from this trial were enough to convince Dr Whitehead and his colleagues to routinely recommend saline nasal spray to their patients with HHT.

“We stress the importance of hydration,” Dr Whitehead said. “We tell them that something as simple as a morning and night saline spray could offer them some benefit.”

Kevin Whitehead, MD

Photo courtesy of the

University of Utah

Health Sciences Center

Results of a phase 2 study suggest a saline nose spray may be as effective as 3 different medicated sprays for preventing epistaxis in patients with hemorrhagic telangiectasia (HHT).

The study was a comparison of bevacizumab, estriol, tranexamic acid, and saline.

The results showed no significant differences in the frequency or duration of epistaxis, and patients in all 4 groups reported improvements in Epistaxis Severity Scores (ESS).

“This research highlights that there could be a benefit even in the simplest of interventions,” said study author Kevin Whitehead, MD, of the University of Utah School of Medicine in Salt Lake City.

“No drug proved to be any better than the saline placebo, but the majority of patients improved over the course of treatment—even those using saline.”

Dr Whitehead and his colleagues reported these results in JAMA.

The study included 121 HHT patients who had experienced HHT-related epistaxis. They were randomized to twice-daily nose sprays with bevacizumab 1% (4 mg/day), estriol 0.1% (0.4 mg/day), tranexamic acid 10% (40 mg/day), or placebo (0.9% saline) for 12 weeks.

Safety

The investigators said nasal symptoms were the most common adverse events, and they occurred in all 4 treatment groups.

Gastrointestinal symptoms, including abdominal pain, nausea, and vomiting, were most common among patients receiving tranexamic acid.

There were no thrombotic complications, episodes of severe hypertension, serious drug-related adverse events, or deaths in any treatment group.

Efficacy

There was no significant difference in epistaxis frequency between the placebo group and the other treatment groups (P=0.97).

After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 for patients in the bevacizumab group, 8.0 for the estriol group, 7.5 for the tranexamic acid group, and 8.0 for the placebo group. At baseline, the median weekly number of bleeding episodes was 10.0, 7.0, 7.8, and 7.0, respectively.

After 12 weeks of treatment, there was no significant difference in epistaxis duration between the placebo group and the other treatment groups (P=0.09).

The median duration of epistaxis per bleeding episode was 3.0 minutes for the bevacizumab group, 4.0 minutes for the estriol group, 6.2 minutes for the tranexamic acid group, and 5.0 minutes for the placebo group. (Bleeding duration was not recorded at baseline.)

After 12 weeks of treatment, there were no significant differences between the treatment groups when it came to hemoglobin levels (P=0.43), ferritin levels (P=0.10), treatment failure (P=0.08), the need for transfusion (P=0.42), or emergency department visits (P=0.72).

Patients in all 4 treatment groups experienced a significant decline in ESS from baseline to week 12 (P<0.001 for time effect).

The median ESS decreased from 5.71 to 3.74 in the placebo group, 5.16 to 3.54 in the bevacizumab group, 5.19 to 3.56 in the estriol group, and 5.43 to 4.06 in the tranexamic acid group. The investigators said the improvement in ESS was clinically significant.

However, the team also said they cannot completely rule out the possibility that symptoms may have improved because of a placebo effect.

What’s more, it could be that some of the drugs tested would work better if taken at a higher dose, or if applied as a gel or polymer that adheres better to the inside of the nasal cavity.

Nevertheless, the results from this trial were enough to convince Dr Whitehead and his colleagues to routinely recommend saline nasal spray to their patients with HHT.

“We stress the importance of hydration,” Dr Whitehead said. “We tell them that something as simple as a morning and night saline spray could offer them some benefit.”

DNA helix

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted orphan drug designation to SB-FIX, a zinc finger nuclease (ZFN)-mediated genome-editing product candidate for the treatment of hemophilia B.

SB-FIX is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.

The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.

The approach is designed is to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.

This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.

Sangamo BioSciences, Inc., the company developing SB-FIX, expects to initiate a phase 1/2 trial of SB-FIX in adults with hemophilia B this year.

“We will enroll adult hemophilia patients into our first clinical trial. However, our goal is to move into pediatric patients, a population we believe could particularly benefit from a treatment that has the potential to provide life-long expression of therapeutic levels of factor IX protein,” said Geoff Nichol, MBChB, Sangamo’s executive vice president of research and development.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

DNA helix

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted orphan drug designation to SB-FIX, a zinc finger nuclease (ZFN)-mediated genome-editing product candidate for the treatment of hemophilia B.

SB-FIX is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.

The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.

The approach is designed is to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.

This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.

Sangamo BioSciences, Inc., the company developing SB-FIX, expects to initiate a phase 1/2 trial of SB-FIX in adults with hemophilia B this year.

“We will enroll adult hemophilia patients into our first clinical trial. However, our goal is to move into pediatric patients, a population we believe could particularly benefit from a treatment that has the potential to provide life-long expression of therapeutic levels of factor IX protein,” said Geoff Nichol, MBChB, Sangamo’s executive vice president of research and development.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

DNA helix

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted orphan drug designation to SB-FIX, a zinc finger nuclease (ZFN)-mediated genome-editing product candidate for the treatment of hemophilia B.

SB-FIX is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.

The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.

The approach is designed is to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.

This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.

Sangamo BioSciences, Inc., the company developing SB-FIX, expects to initiate a phase 1/2 trial of SB-FIX in adults with hemophilia B this year.

“We will enroll adult hemophilia patients into our first clinical trial. However, our goal is to move into pediatric patients, a population we believe could particularly benefit from a treatment that has the potential to provide life-long expression of therapeutic levels of factor IX protein,” said Geoff Nichol, MBChB, Sangamo’s executive vice president of research and development.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

HSCT preparation

Photo by Chad McNeeley

New research suggests hematopoietic stem cell transplant (HSCT) may increase the molecular age of peripheral blood T cells.

The study showed an increase in peripheral blood T-cell senescence in patients with hematologic malignancies who were treated with autologous (auto-) or allogeneic (allo-) HSCT.

The patients had elevated levels of p16INK4a, a known marker of cellular senescence.

Auto-HSCT in particular had a strong effect on p16INK4a, increasing the expression of this marker to a degree comparable to 30 years of chronological aging.

Researchers reported these findings in EBioMedicine.

“We know that transplant is life-prolonging, and, in many cases, it’s life-saving for many patients with blood cancers and other disorders,” said study author William Wood, MD, of the University of North Carolina School of Medicine in Chapel Hill.

“At the same time, we’re increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems or even in helping choose which patients are best candidates for transplantation.”

With this in mind, Dr Wood and his colleagues looked at levels of p16INK4a in 63 patients who underwent auto- or allo-HSCT to treat myeloma, lymphoma, or leukemia. The researchers assessed p16INK4a expression in T cells before HSCT and 6 months after.

Among auto-HSCT recipients, there were no baseline characteristics associated with pre-transplant p16INK4a expression.

However, allo-HSCT recipients had significantly higher pre-transplant p16INK4a levels the more cycles of chemotherapy they received before transplant (P=0.003), if they had previously undergone auto-HSCT (P=0.01), and if they had been exposed to alkylating agents (P=0.01).

After transplant, allo-HSCT recipients had a 1.93-fold increase in p16INK4a expression (P=0.0004), and auto-HSCT recipients had a 3.05-fold increase (P=0.002).

The researchers said the measured change in p16INK4a from pre- to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure.

The researchers also pointed out that this study does not show a clear connection between changes in p16INK4a levels and the actual function of peripheral blood T cells, but they did say that p16INK4a is “arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration.”

So the results of this research suggest the forced bone marrow repopulation associated with HSCT accelerates the molecular aging of peripheral blood T cells.

“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said study author Norman Sharpless, MD, of the University of North Carolina School of Medicine.

“We know that, years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”

HSCT preparation

Photo by Chad McNeeley

New research suggests hematopoietic stem cell transplant (HSCT) may increase the molecular age of peripheral blood T cells.

The study showed an increase in peripheral blood T-cell senescence in patients with hematologic malignancies who were treated with autologous (auto-) or allogeneic (allo-) HSCT.

The patients had elevated levels of p16INK4a, a known marker of cellular senescence.

Auto-HSCT in particular had a strong effect on p16INK4a, increasing the expression of this marker to a degree comparable to 30 years of chronological aging.

Researchers reported these findings in EBioMedicine.

“We know that transplant is life-prolonging, and, in many cases, it’s life-saving for many patients with blood cancers and other disorders,” said study author William Wood, MD, of the University of North Carolina School of Medicine in Chapel Hill.

“At the same time, we’re increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems or even in helping choose which patients are best candidates for transplantation.”

With this in mind, Dr Wood and his colleagues looked at levels of p16INK4a in 63 patients who underwent auto- or allo-HSCT to treat myeloma, lymphoma, or leukemia. The researchers assessed p16INK4a expression in T cells before HSCT and 6 months after.

Among auto-HSCT recipients, there were no baseline characteristics associated with pre-transplant p16INK4a expression.

However, allo-HSCT recipients had significantly higher pre-transplant p16INK4a levels the more cycles of chemotherapy they received before transplant (P=0.003), if they had previously undergone auto-HSCT (P=0.01), and if they had been exposed to alkylating agents (P=0.01).

After transplant, allo-HSCT recipients had a 1.93-fold increase in p16INK4a expression (P=0.0004), and auto-HSCT recipients had a 3.05-fold increase (P=0.002).

The researchers said the measured change in p16INK4a from pre- to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure.

The researchers also pointed out that this study does not show a clear connection between changes in p16INK4a levels and the actual function of peripheral blood T cells, but they did say that p16INK4a is “arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration.”

So the results of this research suggest the forced bone marrow repopulation associated with HSCT accelerates the molecular aging of peripheral blood T cells.

“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said study author Norman Sharpless, MD, of the University of North Carolina School of Medicine.

“We know that, years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”

HSCT preparation

Photo by Chad McNeeley

New research suggests hematopoietic stem cell transplant (HSCT) may increase the molecular age of peripheral blood T cells.

The study showed an increase in peripheral blood T-cell senescence in patients with hematologic malignancies who were treated with autologous (auto-) or allogeneic (allo-) HSCT.

The patients had elevated levels of p16INK4a, a known marker of cellular senescence.

Auto-HSCT in particular had a strong effect on p16INK4a, increasing the expression of this marker to a degree comparable to 30 years of chronological aging.

Researchers reported these findings in EBioMedicine.

“We know that transplant is life-prolonging, and, in many cases, it’s life-saving for many patients with blood cancers and other disorders,” said study author William Wood, MD, of the University of North Carolina School of Medicine in Chapel Hill.

“At the same time, we’re increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems or even in helping choose which patients are best candidates for transplantation.”

With this in mind, Dr Wood and his colleagues looked at levels of p16INK4a in 63 patients who underwent auto- or allo-HSCT to treat myeloma, lymphoma, or leukemia. The researchers assessed p16INK4a expression in T cells before HSCT and 6 months after.

Among auto-HSCT recipients, there were no baseline characteristics associated with pre-transplant p16INK4a expression.

However, allo-HSCT recipients had significantly higher pre-transplant p16INK4a levels the more cycles of chemotherapy they received before transplant (P=0.003), if they had previously undergone auto-HSCT (P=0.01), and if they had been exposed to alkylating agents (P=0.01).

After transplant, allo-HSCT recipients had a 1.93-fold increase in p16INK4a expression (P=0.0004), and auto-HSCT recipients had a 3.05-fold increase (P=0.002).

The researchers said the measured change in p16INK4a from pre- to post-HSCT in allogeneic recipients likely underestimates the age-promoting effects of HSCT, given that the pre-HSCT levels were elevated in the recipients from prior therapeutic exposure.

The researchers also pointed out that this study does not show a clear connection between changes in p16INK4a levels and the actual function of peripheral blood T cells, but they did say that p16INK4a is “arguably one of the best in vivo markers of cellular senescence and is directly associated with age-related deterioration.”

So the results of this research suggest the forced bone marrow repopulation associated with HSCT accelerates the molecular aging of peripheral blood T cells.

“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said study author Norman Sharpless, MD, of the University of North Carolina School of Medicine.

“We know that, years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”

Doctor evaluating a patient

Photo courtesy of the CDC

Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.

This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.

Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.

The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.

Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.

Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.

Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.

Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.

The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.

Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).

Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.

The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.

Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.

Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.

Doctor evaluating a patient

Photo courtesy of the CDC

Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.

This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.

Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.

The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.

Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.

Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.

Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.

Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.

The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.

Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).

Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.

The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.

Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.

Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.

Doctor evaluating a patient

Photo courtesy of the CDC

Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.

This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.

Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.

The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.

Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.

Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.

Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.

Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.

The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.

Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).

Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.

The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.

Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.

Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.

Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.

The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.

“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”

Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.

“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”

For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.

The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.

Dynamic instability

Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.

Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.

These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.

The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.

Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.

As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.

The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.

Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.

The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.

“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”

Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.

“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”

For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.

The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.

Dynamic instability

Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.

Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.

These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.

The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.

Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.

As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.

The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.

Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.

The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.

“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”

Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.

“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”

For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.

The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.

Dynamic instability

Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.

Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.

These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.

The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.

Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.

As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.

The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.