Hematology Times

Lab mouse

Researchers believe they may have discovered why medical interventions that succeed in mice don’t always translate to the clinic.

The team said the fact that lab mice are raised in pathogen-free environments may contribute to the differences in immune system development between lab mice and humans.

But co-housing lab mice with mice from pet stores can produce “dirty” mouse models that may better reflect the immune systems of adult humans.

David Masopust, PhD, of the University of Minnesota in Minneapolis, and his colleagues described these findings in a letter to Nature.

The researchers first explored immunological differences between lab mice and humans by analyzing cervical tissue specimens from adults of each species.

The team found that lab mice had fewer, less diverse, and less widely distributed memory T cells when compared with humans.

The immune systems of lab mice more closely resembled those of human infants, particularly with regard to the number and tissue distribution of memory T cells.

The researchers performed a similar analysis on tissues from lab mice and from mice found in barn or pet store environments.

The non-lab mice had immune systems more like those of adult humans, which suggests the variation in microbial environment—and not the species difference—could account for the immune system differences.

The researchers then set out to determine if the immune systems of lab mice with little exposure to environmental microbes could change when exposed to a different environment.

They co-housed lab mice with healthy mice raised in a pet store. After 8 weeks, analyses of the lab mice revealed patterns of T cells and other immune system components that more closely matched the pet store mice as well as adult humans.

The researchers said these findings suggest that “dirty” mice may model the human immune system more closely than typical lab mice and could be studied to learn more about the role of environment and genetics in the development of the human immune system.

Lab mouse

Researchers believe they may have discovered why medical interventions that succeed in mice don’t always translate to the clinic.

The team said the fact that lab mice are raised in pathogen-free environments may contribute to the differences in immune system development between lab mice and humans.

But co-housing lab mice with mice from pet stores can produce “dirty” mouse models that may better reflect the immune systems of adult humans.

David Masopust, PhD, of the University of Minnesota in Minneapolis, and his colleagues described these findings in a letter to Nature.

The researchers first explored immunological differences between lab mice and humans by analyzing cervical tissue specimens from adults of each species.

The team found that lab mice had fewer, less diverse, and less widely distributed memory T cells when compared with humans.

The immune systems of lab mice more closely resembled those of human infants, particularly with regard to the number and tissue distribution of memory T cells.

The researchers performed a similar analysis on tissues from lab mice and from mice found in barn or pet store environments.

The non-lab mice had immune systems more like those of adult humans, which suggests the variation in microbial environment—and not the species difference—could account for the immune system differences.

The researchers then set out to determine if the immune systems of lab mice with little exposure to environmental microbes could change when exposed to a different environment.

They co-housed lab mice with healthy mice raised in a pet store. After 8 weeks, analyses of the lab mice revealed patterns of T cells and other immune system components that more closely matched the pet store mice as well as adult humans.

The researchers said these findings suggest that “dirty” mice may model the human immune system more closely than typical lab mice and could be studied to learn more about the role of environment and genetics in the development of the human immune system.

Lab mouse

Researchers believe they may have discovered why medical interventions that succeed in mice don’t always translate to the clinic.

The team said the fact that lab mice are raised in pathogen-free environments may contribute to the differences in immune system development between lab mice and humans.

But co-housing lab mice with mice from pet stores can produce “dirty” mouse models that may better reflect the immune systems of adult humans.

David Masopust, PhD, of the University of Minnesota in Minneapolis, and his colleagues described these findings in a letter to Nature.

The researchers first explored immunological differences between lab mice and humans by analyzing cervical tissue specimens from adults of each species.

The team found that lab mice had fewer, less diverse, and less widely distributed memory T cells when compared with humans.

The immune systems of lab mice more closely resembled those of human infants, particularly with regard to the number and tissue distribution of memory T cells.

The researchers performed a similar analysis on tissues from lab mice and from mice found in barn or pet store environments.

The non-lab mice had immune systems more like those of adult humans, which suggests the variation in microbial environment—and not the species difference—could account for the immune system differences.

The researchers then set out to determine if the immune systems of lab mice with little exposure to environmental microbes could change when exposed to a different environment.

They co-housed lab mice with healthy mice raised in a pet store. After 8 weeks, analyses of the lab mice revealed patterns of T cells and other immune system components that more closely matched the pet store mice as well as adult humans.

The researchers said these findings suggest that “dirty” mice may model the human immune system more closely than typical lab mice and could be studied to learn more about the role of environment and genetics in the development of the human immune system.

Red blood cells

Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.

The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.

To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.

At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).

These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.

“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.

“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”

This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Researchers plan to monitor patients for safety and durability of effect for 5 years.

Results

A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 10¹² vg/kg, one at 2 x 10¹³ vg/kg, and six at 6 x 10¹³ vg/kg.

At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.

At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.

One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.

Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.

And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.

Liver function

The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.

Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.

Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.

In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.

After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.

BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.

“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.

“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”

BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.

Red blood cells

Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.

The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.

To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.

At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).

These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.

“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.

“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”

This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Researchers plan to monitor patients for safety and durability of effect for 5 years.

Results

A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 10¹² vg/kg, one at 2 x 10¹³ vg/kg, and six at 6 x 10¹³ vg/kg.

At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.

At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.

One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.

Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.

And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.

Liver function

The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.

Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.

Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.

In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.

After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.

BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.

“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.

“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”

BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.

Red blood cells

Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.

The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.

To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.

At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).

These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.

“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.

“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”

This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Researchers plan to monitor patients for safety and durability of effect for 5 years.

Results

A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 10¹² vg/kg, one at 2 x 10¹³ vg/kg, and six at 6 x 10¹³ vg/kg.

At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.

At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.

One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.

Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.

And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.

Liver function

The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.

Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.

Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.

In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.

After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.

BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.

“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.

“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”

BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (T_EM) and a concomitant increase in effector T cells (T_eff) during therapy.

This “T_EM to T_eff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), T_EM cells (CD45RO+CCR7-), and T_eff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in T_EM cells (P=0.001) and a significant increase in T_eff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in T_EM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in T_eff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of T_EM cells and induction of T_eff cells—the T_EM to T_eff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.”

*Information in the abstract differs from that presented at the meeting.

AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (T_EM) and a concomitant increase in effector T cells (T_eff) during therapy.

This “T_EM to T_eff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), T_EM cells (CD45RO+CCR7-), and T_eff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in T_EM cells (P=0.001) and a significant increase in T_eff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in T_EM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in T_eff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of T_EM cells and induction of T_eff cells—the T_EM to T_eff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.”

*Information in the abstract differs from that presented at the meeting.

AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (T_EM) and a concomitant increase in effector T cells (T_eff) during therapy.

This “T_EM to T_eff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), T_EM cells (CD45RO+CCR7-), and T_eff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in T_EM cells (P=0.001) and a significant increase in T_eff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in T_EM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in T_eff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of T_EM cells and induction of T_eff cells—the T_EM to T_eff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.”

*Information in the abstract differs from that presented at the meeting.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Bottles of warfarin

Photo courtesy of NIGMS

Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).

However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.

Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.

The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.

So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.

The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.

Overall results

The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.

The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.

Aspirin and intracranial bleeding

When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).

But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).

Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).

In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).

INR and iTTR

Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.

This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).

Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).

This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).

The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).

For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.

Bottles of warfarin

Photo courtesy of NIGMS

Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).

However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.

Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.

The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.

So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.

The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.

Overall results

The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.

The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.

Aspirin and intracranial bleeding

When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).

But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).

Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).

In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).

INR and iTTR

Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.

This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).

Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).

This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).

The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).

For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.

Bottles of warfarin

Photo courtesy of NIGMS

Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).

However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.

Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.

The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.

So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.

The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.

Overall results

The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.

The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.

Aspirin and intracranial bleeding

When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).

But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).

Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).

In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).

INR and iTTR

Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.

This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).

Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).

This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).

The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).

For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

 

 

Attendees in session at

2016 AACR Annual Meeting

© AACR/Todd Buchanan

 

NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.

The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.

In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.

The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.

In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.

These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.

Patients and study design

The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.

The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.

In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.

In Arm 1 (n=12), patients received rituximab (at 375 mg/m²) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).

In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).

The first patient treated on this trial received 250 mg/m² of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.

The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.

Safety

Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.

In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).

Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).

The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.

The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.

All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.

Efficacy

Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.

The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.

Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.

For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees in session at

2016 AACR Annual Meeting

© AACR/Todd Buchanan

 

NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.

The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.

In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.

The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.

In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.

These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.

Patients and study design

The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.

The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.

In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.

In Arm 1 (n=12), patients received rituximab (at 375 mg/m²) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).

In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).

The first patient treated on this trial received 250 mg/m² of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.

The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.

Safety

Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.

In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).

Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).

The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.

The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.

All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.

Efficacy

Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.

The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.

Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.

For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees in session at

2016 AACR Annual Meeting

© AACR/Todd Buchanan

 

NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.

The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.

In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.

The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.

In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.

These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.

Patients and study design

The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.

The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.

In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.

In Arm 1 (n=12), patients received rituximab (at 375 mg/m²) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).

In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).

The first patient treated on this trial received 250 mg/m² of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.

The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.

Safety

Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.

In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).

Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).

The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.

The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.

All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.

Efficacy

Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.

The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.

Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.

For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.

*Information in the abstract differs from that presented at the meeting.

Micrograph showing ALL

Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.

The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.

During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).

The researchers described Monovar in Nature Methods.

“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”

Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.

The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.

In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.

The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).

The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).

Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.

The researchers also believe Monovar could be used for studies in a range of biomedical fields.

“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.

“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”

Micrograph showing ALL

Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.

The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.

During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).

The researchers described Monovar in Nature Methods.

“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”

Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.

The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.

In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.

The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).

The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).

Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.

The researchers also believe Monovar could be used for studies in a range of biomedical fields.

“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.

“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”

Micrograph showing ALL

Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.

The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.

During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).

The researchers described Monovar in Nature Methods.

“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”

Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.

The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.

In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.

The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).

The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).

Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.

The researchers also believe Monovar could be used for studies in a range of biomedical fields.

“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.

“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”

 

 

Micrograph showing

follicular lymphoma

 

NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.

In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.

This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.

In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.

“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.

Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.

The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.

Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).

At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.

In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).

“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”

Safety

All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.

The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.

In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.

Efficacy

The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).

In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).

CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.

Furthermore, treated and untreated tumors decreased in volume across all dose groups.

At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).

In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.

However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).

Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).

The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.

 

 

Micrograph showing

follicular lymphoma

 

NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.

In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.

This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.

In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.

“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.

Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.

The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.

Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).

At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.

In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).

“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”

Safety

All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.

The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.

In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.

Efficacy

The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).

In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).

CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.

Furthermore, treated and untreated tumors decreased in volume across all dose groups.

At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).

In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.

However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).

Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).

The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.

 

 

Micrograph showing

follicular lymphoma

 

NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.

In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.

This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.

In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.

“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.

Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.

The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.

Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).

At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.

In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).

“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”

Safety

All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.

The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.

In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.

Efficacy

The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).

In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).

CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.

Furthermore, treated and untreated tumors decreased in volume across all dose groups.

At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).

In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.

However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).

Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).

The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.