HT Staff

Micrograph showing

CMV infection

A new study indicates that transferring low doses of immune cells may be sufficient to protect against cytomegalovirus (CMV) infection in patients receiving allogeneic stem cell transplant.

The researchers noted that the adoptive transfer of donor-derived, virus-specific, memory T cells is a promising strategy for treating and preventing CMV infection.

But transferring too many of these cells can increase the risk of graft-vs-host disease.

So Christian Stemberger, PhD, of Technische Universitaet Muenchen in Germany, and his colleagues set out to establish a lower limit for successful adoptive T-cell therapy.

The team reported their results—observed in mice and 2 human patients—in Blood.

The researchers first conducted low-dose CD8+ T-cell transfers in the murine Listeria monocytogenes infection model.

And they found these MHC-Streptamer-enriched, antigen-specific, CD62L^hi, CD8⁺ memory T cells proliferated, differentiated, and protected against Listeria monocytogenes infections.

“The most astonishing result was that the offspring cells of just 1 transferred donor cell were enough to completely protect the animals,” Dr Stemberger said.

Next, the researchers used virus-specific T cells to treat 2 critically ill pediatric patients—1 with severe combined immunodeficiency (SCID) and the other with B-cell acute lymphoblastic leukemia.

The patients had received allogeneic transplants and subsequently developed CMV infections.

The patients received low-dose transfers of Streptamer-enriched, CMV-specific, CD8⁺ T cells—3750 cells per kilogram of body weight for the SCID patient and 5130 cells per kilogram of body weight for the leukemia patient.

In both patients, the researchers observed “strong, pathogen-specific T-cell expansion.” The CMV-specific, CD8⁺ T cells proliferated, and the CMV viral load decreased. Furthermore, neither patient developed graft-vs-host disease.

“It is a great advantage that even just a few cells can provide protection [from CMV],” said study author Michael Neuenhahn, Dr med, also of Technische Universitaet Muenchen.

“This means that the cells can be used for preventive treatment in low doses that are gentler on the organism.”

The researchers are now testing the potential of the CMV-specific, CD8⁺ T cells in a clinical study.

Micrograph showing

CMV infection

A new study indicates that transferring low doses of immune cells may be sufficient to protect against cytomegalovirus (CMV) infection in patients receiving allogeneic stem cell transplant.

The researchers noted that the adoptive transfer of donor-derived, virus-specific, memory T cells is a promising strategy for treating and preventing CMV infection.

But transferring too many of these cells can increase the risk of graft-vs-host disease.

So Christian Stemberger, PhD, of Technische Universitaet Muenchen in Germany, and his colleagues set out to establish a lower limit for successful adoptive T-cell therapy.

The team reported their results—observed in mice and 2 human patients—in Blood.

The researchers first conducted low-dose CD8+ T-cell transfers in the murine Listeria monocytogenes infection model.

And they found these MHC-Streptamer-enriched, antigen-specific, CD62L^hi, CD8⁺ memory T cells proliferated, differentiated, and protected against Listeria monocytogenes infections.

“The most astonishing result was that the offspring cells of just 1 transferred donor cell were enough to completely protect the animals,” Dr Stemberger said.

Next, the researchers used virus-specific T cells to treat 2 critically ill pediatric patients—1 with severe combined immunodeficiency (SCID) and the other with B-cell acute lymphoblastic leukemia.

The patients had received allogeneic transplants and subsequently developed CMV infections.

The patients received low-dose transfers of Streptamer-enriched, CMV-specific, CD8⁺ T cells—3750 cells per kilogram of body weight for the SCID patient and 5130 cells per kilogram of body weight for the leukemia patient.

In both patients, the researchers observed “strong, pathogen-specific T-cell expansion.” The CMV-specific, CD8⁺ T cells proliferated, and the CMV viral load decreased. Furthermore, neither patient developed graft-vs-host disease.

“It is a great advantage that even just a few cells can provide protection [from CMV],” said study author Michael Neuenhahn, Dr med, also of Technische Universitaet Muenchen.

“This means that the cells can be used for preventive treatment in low doses that are gentler on the organism.”

The researchers are now testing the potential of the CMV-specific, CD8⁺ T cells in a clinical study.

Micrograph showing

CMV infection

A new study indicates that transferring low doses of immune cells may be sufficient to protect against cytomegalovirus (CMV) infection in patients receiving allogeneic stem cell transplant.

The researchers noted that the adoptive transfer of donor-derived, virus-specific, memory T cells is a promising strategy for treating and preventing CMV infection.

But transferring too many of these cells can increase the risk of graft-vs-host disease.

So Christian Stemberger, PhD, of Technische Universitaet Muenchen in Germany, and his colleagues set out to establish a lower limit for successful adoptive T-cell therapy.

The team reported their results—observed in mice and 2 human patients—in Blood.

The researchers first conducted low-dose CD8+ T-cell transfers in the murine Listeria monocytogenes infection model.

And they found these MHC-Streptamer-enriched, antigen-specific, CD62L^hi, CD8⁺ memory T cells proliferated, differentiated, and protected against Listeria monocytogenes infections.

“The most astonishing result was that the offspring cells of just 1 transferred donor cell were enough to completely protect the animals,” Dr Stemberger said.

Next, the researchers used virus-specific T cells to treat 2 critically ill pediatric patients—1 with severe combined immunodeficiency (SCID) and the other with B-cell acute lymphoblastic leukemia.

The patients had received allogeneic transplants and subsequently developed CMV infections.

The patients received low-dose transfers of Streptamer-enriched, CMV-specific, CD8⁺ T cells—3750 cells per kilogram of body weight for the SCID patient and 5130 cells per kilogram of body weight for the leukemia patient.

In both patients, the researchers observed “strong, pathogen-specific T-cell expansion.” The CMV-specific, CD8⁺ T cells proliferated, and the CMV viral load decreased. Furthermore, neither patient developed graft-vs-host disease.

“It is a great advantage that even just a few cells can provide protection [from CMV],” said study author Michael Neuenhahn, Dr med, also of Technische Universitaet Muenchen.

“This means that the cells can be used for preventive treatment in low doses that are gentler on the organism.”

The researchers are now testing the potential of the CMV-specific, CD8⁺ T cells in a clinical study.

Attendees at ASCO 2014

©ASCO/Brian Powers

CHICAGO—Hepatitis C reactivation does not worsen survival outcomes for HIV-positive patients diagnosed with lymphoma, new research indicates.

The study showed these patients can tolerate chemotherapy without adverse outcomes and are therefore eligible for aggressive treatment.

They should be closely monitored, however, according to study investigator Stefan K. Barta, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr Barta and his colleagues presented results observed in HIV-positive lymphoma patients at the 2014 ASCO Annual Meeting as abstract 8578.

The team noted that more than a quarter of HIV-positive patients are also infected with the hepatitis C virus (HCV), which may complicate treatment and care decisions after a cancer diagnosis.

“Patients undergoing chemotherapy can experience reactivation of the hepatitis C virus, which, in turn, can lead to liver failure,” Dr Barta said. “This means we have to dose-reduce chemotherapy, which could negatively affect outcomes.”

In addition, HIV-positive patients often take a host of other medications, including anti-retrovirals, which makes them especially vulnerable to side effects.

However, Dr Barta said these potential risks shouldn’t deter oncologists from treating these patients with chemotherapy because he and his colleagues found that reactivation of HCV did not worsen survival outcomes in this population.

The researchers analyzed the medical records of 190 HIV-positive patients who had been diagnosed with lymphoma at the Albert Einstein Cancer Center in Bronx, New York, from 1997 to 2013. Patients with primary central nervous system lymphomas were excluded.

Fifty-three (28%) eligible patients were also infected with HCV. The virus reactivated in 17 of those patients, or about one-third of the patient population infected with HCV, during treatment.

Patients infected with HCV had an overall survival of 59.7 months, compared to 88.6 months for patients with neither HCV nor hepatitis B virus (HBV).

However, that survival advantage vanished when the researchers adjusted for variables including age, sex, race, CD4 count, the presence of cirrhosis, type of lymphoma, and levels of lactate dehydrogenase (LDH).

The multivariate analysis showed that co-infection with HCV was not associated with lower overall survival in lymphoma patients.

At the same time, the researchers did find worse overall survival outcomes associated with low CD4 count (below 100 cells/cubic millimeter), a diagnosis of non-Hodgkin lymphoma, advanced stage disease, LDH levels over 190, or cirrhosis.

Dr Barta said he hopes this research will open cancer trials up to an understudied patient population. HIV-positive patients with HCV are often excluded from these trials because of concerns about liver failure and toxicity arising from the interaction of retroviral medications with chemotherapy.

“This is really important for a large proportion of patients,” he said. “We want to assure researchers that these patients, as long as they have adequate liver function, should also be enrolled in clinical trials.”

Attendees at ASCO 2014

©ASCO/Brian Powers

CHICAGO—Hepatitis C reactivation does not worsen survival outcomes for HIV-positive patients diagnosed with lymphoma, new research indicates.

The study showed these patients can tolerate chemotherapy without adverse outcomes and are therefore eligible for aggressive treatment.

They should be closely monitored, however, according to study investigator Stefan K. Barta, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr Barta and his colleagues presented results observed in HIV-positive lymphoma patients at the 2014 ASCO Annual Meeting as abstract 8578.

The team noted that more than a quarter of HIV-positive patients are also infected with the hepatitis C virus (HCV), which may complicate treatment and care decisions after a cancer diagnosis.

“Patients undergoing chemotherapy can experience reactivation of the hepatitis C virus, which, in turn, can lead to liver failure,” Dr Barta said. “This means we have to dose-reduce chemotherapy, which could negatively affect outcomes.”

In addition, HIV-positive patients often take a host of other medications, including anti-retrovirals, which makes them especially vulnerable to side effects.

However, Dr Barta said these potential risks shouldn’t deter oncologists from treating these patients with chemotherapy because he and his colleagues found that reactivation of HCV did not worsen survival outcomes in this population.

The researchers analyzed the medical records of 190 HIV-positive patients who had been diagnosed with lymphoma at the Albert Einstein Cancer Center in Bronx, New York, from 1997 to 2013. Patients with primary central nervous system lymphomas were excluded.

Fifty-three (28%) eligible patients were also infected with HCV. The virus reactivated in 17 of those patients, or about one-third of the patient population infected with HCV, during treatment.

Patients infected with HCV had an overall survival of 59.7 months, compared to 88.6 months for patients with neither HCV nor hepatitis B virus (HBV).

However, that survival advantage vanished when the researchers adjusted for variables including age, sex, race, CD4 count, the presence of cirrhosis, type of lymphoma, and levels of lactate dehydrogenase (LDH).

The multivariate analysis showed that co-infection with HCV was not associated with lower overall survival in lymphoma patients.

At the same time, the researchers did find worse overall survival outcomes associated with low CD4 count (below 100 cells/cubic millimeter), a diagnosis of non-Hodgkin lymphoma, advanced stage disease, LDH levels over 190, or cirrhosis.

Dr Barta said he hopes this research will open cancer trials up to an understudied patient population. HIV-positive patients with HCV are often excluded from these trials because of concerns about liver failure and toxicity arising from the interaction of retroviral medications with chemotherapy.

“This is really important for a large proportion of patients,” he said. “We want to assure researchers that these patients, as long as they have adequate liver function, should also be enrolled in clinical trials.”

Attendees at ASCO 2014

©ASCO/Brian Powers

CHICAGO—Hepatitis C reactivation does not worsen survival outcomes for HIV-positive patients diagnosed with lymphoma, new research indicates.

The study showed these patients can tolerate chemotherapy without adverse outcomes and are therefore eligible for aggressive treatment.

They should be closely monitored, however, according to study investigator Stefan K. Barta, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr Barta and his colleagues presented results observed in HIV-positive lymphoma patients at the 2014 ASCO Annual Meeting as abstract 8578.

The team noted that more than a quarter of HIV-positive patients are also infected with the hepatitis C virus (HCV), which may complicate treatment and care decisions after a cancer diagnosis.

“Patients undergoing chemotherapy can experience reactivation of the hepatitis C virus, which, in turn, can lead to liver failure,” Dr Barta said. “This means we have to dose-reduce chemotherapy, which could negatively affect outcomes.”

In addition, HIV-positive patients often take a host of other medications, including anti-retrovirals, which makes them especially vulnerable to side effects.

However, Dr Barta said these potential risks shouldn’t deter oncologists from treating these patients with chemotherapy because he and his colleagues found that reactivation of HCV did not worsen survival outcomes in this population.

The researchers analyzed the medical records of 190 HIV-positive patients who had been diagnosed with lymphoma at the Albert Einstein Cancer Center in Bronx, New York, from 1997 to 2013. Patients with primary central nervous system lymphomas were excluded.

Fifty-three (28%) eligible patients were also infected with HCV. The virus reactivated in 17 of those patients, or about one-third of the patient population infected with HCV, during treatment.

Patients infected with HCV had an overall survival of 59.7 months, compared to 88.6 months for patients with neither HCV nor hepatitis B virus (HBV).

However, that survival advantage vanished when the researchers adjusted for variables including age, sex, race, CD4 count, the presence of cirrhosis, type of lymphoma, and levels of lactate dehydrogenase (LDH).

The multivariate analysis showed that co-infection with HCV was not associated with lower overall survival in lymphoma patients.

At the same time, the researchers did find worse overall survival outcomes associated with low CD4 count (below 100 cells/cubic millimeter), a diagnosis of non-Hodgkin lymphoma, advanced stage disease, LDH levels over 190, or cirrhosis.

Dr Barta said he hopes this research will open cancer trials up to an understudied patient population. HIV-positive patients with HCV are often excluded from these trials because of concerns about liver failure and toxicity arising from the interaction of retroviral medications with chemotherapy.

“This is really important for a large proportion of patients,” he said. “We want to assure researchers that these patients, as long as they have adequate liver function, should also be enrolled in clinical trials.”

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) is taking additional action to warn the public about the risk of venous thromboembolism (VTE) associated with the use of testosterone products.

The agency is now requiring manufacturers to include a general warning in the drug labeling of all approved testosterone products about the risk of VTE these products pose.

The risk is already included in the labeling as a possible consequence of polycythemia, which sometimes occurs with testosterone treatment.

But there have been post-market reports of VTE unrelated to polycythemia.

So the FDA has mandated the label change to provide a more general warning and ensure the risk of VTE is described consistently in the labeling of all approved testosterone products.

This new warning is not related to FDA’s ongoing evaluation of the possible risk of stroke, heart attack, and death in patients taking testosterone products.

The agency is currently evaluating the potential risk of these events, which are described in the Drug Safety Communication posted on January 31, 2014.

Testosterone products are FDA-approved for use in men who lack testosterone or have low testosterone levels in conjunction with an associated medical condition.

The FDA is asking healthcare professionals and consumers to report any adverse reactions related to testosterone products to the agency’s MedWatch Safety Information and Adverse Event Reporting program.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) is taking additional action to warn the public about the risk of venous thromboembolism (VTE) associated with the use of testosterone products.

The agency is now requiring manufacturers to include a general warning in the drug labeling of all approved testosterone products about the risk of VTE these products pose.

The risk is already included in the labeling as a possible consequence of polycythemia, which sometimes occurs with testosterone treatment.

But there have been post-market reports of VTE unrelated to polycythemia.

So the FDA has mandated the label change to provide a more general warning and ensure the risk of VTE is described consistently in the labeling of all approved testosterone products.

This new warning is not related to FDA’s ongoing evaluation of the possible risk of stroke, heart attack, and death in patients taking testosterone products.

The agency is currently evaluating the potential risk of these events, which are described in the Drug Safety Communication posted on January 31, 2014.

Testosterone products are FDA-approved for use in men who lack testosterone or have low testosterone levels in conjunction with an associated medical condition.

The FDA is asking healthcare professionals and consumers to report any adverse reactions related to testosterone products to the agency’s MedWatch Safety Information and Adverse Event Reporting program.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) is taking additional action to warn the public about the risk of venous thromboembolism (VTE) associated with the use of testosterone products.

The agency is now requiring manufacturers to include a general warning in the drug labeling of all approved testosterone products about the risk of VTE these products pose.

The risk is already included in the labeling as a possible consequence of polycythemia, which sometimes occurs with testosterone treatment.

But there have been post-market reports of VTE unrelated to polycythemia.

So the FDA has mandated the label change to provide a more general warning and ensure the risk of VTE is described consistently in the labeling of all approved testosterone products.

This new warning is not related to FDA’s ongoing evaluation of the possible risk of stroke, heart attack, and death in patients taking testosterone products.

The agency is currently evaluating the potential risk of these events, which are described in the Drug Safety Communication posted on January 31, 2014.

Testosterone products are FDA-approved for use in men who lack testosterone or have low testosterone levels in conjunction with an associated medical condition.

The FDA is asking healthcare professionals and consumers to report any adverse reactions related to testosterone products to the agency’s MedWatch Safety Information and Adverse Event Reporting program.

Lab mouse

Scientists say they’ve identified a tumor-associated lipid that successfully stimulates T cells to kill leukemia cells in vitro and in vivo.

The team noted that certain T cells can recognize the presentation of self-derived lipids on the CD1c protein.

These T cells are commonly found in healthy individuals and are known to kill transformed hematopoietic cells.

However, their antigen specificity and potential antileukemic effects have not been well characterized.

So Gennaro De Libero, MD, PhD, of the University Hospital Basel in Switzerland, and his colleagues analyzed these cells and reported their findings in The Journal of Experimental Medicine.

The researchers discovered that CD1c self-reactive T cells recognize a novel class of self-lipids called methyl-lysophosphatidic acids (mLPAs), which were abundant in several human leukemias.

These mLPAs are the first example of lipid tumor-associated antigens (TAAs). TAAs are produced by tumors and stimulate T cells that can kill leukemia cells.

However, protein TAA accumulation can be drastically reduced by variant leukemia cells. And some TAAs may change their structure, which prevents recognition by T cells and facilitates tumor evasion.

mLPAs, on the other hand, do not change their structure and remain abundant in leukemia cells.

Furthermore, Dr De Libero and his colleagues found they could isolate the T cells that recognize and kill mLPA-expressing leukemia cells in in vitro tests.

And when the team transplanted the T cells into mice, the cells displayed therapeutic efficacy against leukemia cells.

The researchers noted that this type of immunotherapy, if proven effective in humans, could be used to help prevent leukemia relapse after chemotherapy or stem cell transplant.

Lab mouse

Scientists say they’ve identified a tumor-associated lipid that successfully stimulates T cells to kill leukemia cells in vitro and in vivo.

The team noted that certain T cells can recognize the presentation of self-derived lipids on the CD1c protein.

These T cells are commonly found in healthy individuals and are known to kill transformed hematopoietic cells.

However, their antigen specificity and potential antileukemic effects have not been well characterized.

So Gennaro De Libero, MD, PhD, of the University Hospital Basel in Switzerland, and his colleagues analyzed these cells and reported their findings in The Journal of Experimental Medicine.

The researchers discovered that CD1c self-reactive T cells recognize a novel class of self-lipids called methyl-lysophosphatidic acids (mLPAs), which were abundant in several human leukemias.

These mLPAs are the first example of lipid tumor-associated antigens (TAAs). TAAs are produced by tumors and stimulate T cells that can kill leukemia cells.

However, protein TAA accumulation can be drastically reduced by variant leukemia cells. And some TAAs may change their structure, which prevents recognition by T cells and facilitates tumor evasion.

mLPAs, on the other hand, do not change their structure and remain abundant in leukemia cells.

Furthermore, Dr De Libero and his colleagues found they could isolate the T cells that recognize and kill mLPA-expressing leukemia cells in in vitro tests.

And when the team transplanted the T cells into mice, the cells displayed therapeutic efficacy against leukemia cells.

The researchers noted that this type of immunotherapy, if proven effective in humans, could be used to help prevent leukemia relapse after chemotherapy or stem cell transplant.

Lab mouse

Scientists say they’ve identified a tumor-associated lipid that successfully stimulates T cells to kill leukemia cells in vitro and in vivo.

The team noted that certain T cells can recognize the presentation of self-derived lipids on the CD1c protein.

These T cells are commonly found in healthy individuals and are known to kill transformed hematopoietic cells.

However, their antigen specificity and potential antileukemic effects have not been well characterized.

So Gennaro De Libero, MD, PhD, of the University Hospital Basel in Switzerland, and his colleagues analyzed these cells and reported their findings in The Journal of Experimental Medicine.

The researchers discovered that CD1c self-reactive T cells recognize a novel class of self-lipids called methyl-lysophosphatidic acids (mLPAs), which were abundant in several human leukemias.

These mLPAs are the first example of lipid tumor-associated antigens (TAAs). TAAs are produced by tumors and stimulate T cells that can kill leukemia cells.

However, protein TAA accumulation can be drastically reduced by variant leukemia cells. And some TAAs may change their structure, which prevents recognition by T cells and facilitates tumor evasion.

mLPAs, on the other hand, do not change their structure and remain abundant in leukemia cells.

Furthermore, Dr De Libero and his colleagues found they could isolate the T cells that recognize and kill mLPA-expressing leukemia cells in in vitro tests.

And when the team transplanted the T cells into mice, the cells displayed therapeutic efficacy against leukemia cells.

The researchers noted that this type of immunotherapy, if proven effective in humans, could be used to help prevent leukemia relapse after chemotherapy or stem cell transplant.

Sharon Cresci, MD

Credit: Robert Boston

Washington University

New research helps explain the higher risk of death observed among some patients taking the anticoagulant clopidogrel after a heart attack.

Researchers identified genetic variants that increased the risk of dying in the year following a first heart attack, but they appeared to do so for different reasons depending on a patient’s race.

Two DNA variants common in African Americans were associated with an increased risk of both bleeding and death.

And in Caucasians, a different variant was linked to additional heart attacks and a higher risk of death.

The variations influence the way patients metabolize clopidogrel and can alter its effectiveness.

These findings were published in Circulation: Cardiovascular Genetics.

“The research is provocative,” said the study’s first author Sharon Cresci, MD, of the Washington University School of Medicine in St Louis.

“Knowing about potential genetic differences based on race can help physicians tailor drugs to patients based on their genetic makeup.”

Clopidogrel is metabolized in the liver, where it is turned into its active form via a group of enzymes called cytochrome P450 (CYP). Although clopidogrel is effective in many patients, earlier studies showed that some patients metabolize the drug better than others.

Indeed, in 2010, the US Food and Drug Administration added a black box warning to labels of clopidogrel after research (which primarily involved Caucasians) showed that people with a particular CYP genetic variant metabolized the drug poorly, which reduced the amount of the drug circulating in the blood. These patients had a higher risk of heart attack and stroke.

Additional studies showed that other CYP gene variants are linked to the rapid metabolism of clopidogrel, and patients with those variants had a higher risk of bleeding. But it has not been clear, until now, that the effects of these particular gene variations can vary by race.

To uncover this finding, Dr Cresci and her colleagues analyzed CYP variants among 2062 Caucasians and 670 African Americans who suffered heart attacks. Nearly 80% of the Caucasians and 65% of the African Americans were prescribed clopidogrel.

The patients were enrolled in a major study known as TRIUMPH (Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health), which was conducted from 2005 to 2008 at 24 US hospitals.

Among patients taking clopidogrel, the 1-year mortality rate for African Americans was 7.2%, compared with 3.6% for Caucasians.

Caucasians who carried the CYP2C19*2 variant, which has been linked to poor metabolism of the drug, had a higher rate of repeat heart attacks and death. However, among African Americans treated with clopidogrel, the CYP2C19*2 variant was not associated with a higher rate of death.

African Americans had higher rates of bleeding and death if they carried either of 2 other variants: CYP1A2*1C or CYP2C19*17, the latter of which has been associated with the rapid metabolism of clopidogrel. Among Caucasians on clopidogrel, neither variant increased the risk of death.

“This is very novel information that begs for more research,” said study author Richard G. Bach, MD, also of Washington University.

Although genetic testing is available to identify CYP variants in a patient’s DNA, these tests are not widely used by cardiologists. Results of the current study suggest this practice may need to be reconsidered.

“This research is an important addition to the field because previous studies looking at CYP gene variants and their effects on risks of repeat heart attacks, bleeding, and death have included predominantly Caucasian patients of European ancestry,” Dr Cresci noted. “There is almost no data, until now, about these variants in African Americans.”

Research examining how genetic variants alter the effectiveness of clopidogrel remains somewhat controversial, Dr Bach said. Many physicians feel that before they can tailor therapy for heart attack patients, more data is needed to prove a clear link between genetic variants and negative health consequences and that tailoring therapy will improve patients’ outcomes, he explained.

His hope is that additional research would provide more definitive conclusions to help physicians choose the best medications for patients after a heart attack and, ultimately, “to reduce the too-high rate of death and disability for patients after a heart attack,” Dr Bach said.

Dr Cresci agreed, adding, “By focusing on genetic differences, we may be able to individualize therapies after heart attacks and achieve the best treatment for each patient.”

Sharon Cresci, MD

Credit: Robert Boston

Washington University

New research helps explain the higher risk of death observed among some patients taking the anticoagulant clopidogrel after a heart attack.

Researchers identified genetic variants that increased the risk of dying in the year following a first heart attack, but they appeared to do so for different reasons depending on a patient’s race.

Two DNA variants common in African Americans were associated with an increased risk of both bleeding and death.

And in Caucasians, a different variant was linked to additional heart attacks and a higher risk of death.

The variations influence the way patients metabolize clopidogrel and can alter its effectiveness.

These findings were published in Circulation: Cardiovascular Genetics.

“The research is provocative,” said the study’s first author Sharon Cresci, MD, of the Washington University School of Medicine in St Louis.

“Knowing about potential genetic differences based on race can help physicians tailor drugs to patients based on their genetic makeup.”

Clopidogrel is metabolized in the liver, where it is turned into its active form via a group of enzymes called cytochrome P450 (CYP). Although clopidogrel is effective in many patients, earlier studies showed that some patients metabolize the drug better than others.

Indeed, in 2010, the US Food and Drug Administration added a black box warning to labels of clopidogrel after research (which primarily involved Caucasians) showed that people with a particular CYP genetic variant metabolized the drug poorly, which reduced the amount of the drug circulating in the blood. These patients had a higher risk of heart attack and stroke.

Additional studies showed that other CYP gene variants are linked to the rapid metabolism of clopidogrel, and patients with those variants had a higher risk of bleeding. But it has not been clear, until now, that the effects of these particular gene variations can vary by race.

To uncover this finding, Dr Cresci and her colleagues analyzed CYP variants among 2062 Caucasians and 670 African Americans who suffered heart attacks. Nearly 80% of the Caucasians and 65% of the African Americans were prescribed clopidogrel.

The patients were enrolled in a major study known as TRIUMPH (Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health), which was conducted from 2005 to 2008 at 24 US hospitals.

Among patients taking clopidogrel, the 1-year mortality rate for African Americans was 7.2%, compared with 3.6% for Caucasians.

Caucasians who carried the CYP2C19*2 variant, which has been linked to poor metabolism of the drug, had a higher rate of repeat heart attacks and death. However, among African Americans treated with clopidogrel, the CYP2C19*2 variant was not associated with a higher rate of death.

African Americans had higher rates of bleeding and death if they carried either of 2 other variants: CYP1A2*1C or CYP2C19*17, the latter of which has been associated with the rapid metabolism of clopidogrel. Among Caucasians on clopidogrel, neither variant increased the risk of death.

“This is very novel information that begs for more research,” said study author Richard G. Bach, MD, also of Washington University.

Although genetic testing is available to identify CYP variants in a patient’s DNA, these tests are not widely used by cardiologists. Results of the current study suggest this practice may need to be reconsidered.

“This research is an important addition to the field because previous studies looking at CYP gene variants and their effects on risks of repeat heart attacks, bleeding, and death have included predominantly Caucasian patients of European ancestry,” Dr Cresci noted. “There is almost no data, until now, about these variants in African Americans.”

Research examining how genetic variants alter the effectiveness of clopidogrel remains somewhat controversial, Dr Bach said. Many physicians feel that before they can tailor therapy for heart attack patients, more data is needed to prove a clear link between genetic variants and negative health consequences and that tailoring therapy will improve patients’ outcomes, he explained.

His hope is that additional research would provide more definitive conclusions to help physicians choose the best medications for patients after a heart attack and, ultimately, “to reduce the too-high rate of death and disability for patients after a heart attack,” Dr Bach said.

Dr Cresci agreed, adding, “By focusing on genetic differences, we may be able to individualize therapies after heart attacks and achieve the best treatment for each patient.”

Sharon Cresci, MD

Credit: Robert Boston

Washington University

New research helps explain the higher risk of death observed among some patients taking the anticoagulant clopidogrel after a heart attack.

Researchers identified genetic variants that increased the risk of dying in the year following a first heart attack, but they appeared to do so for different reasons depending on a patient’s race.

Two DNA variants common in African Americans were associated with an increased risk of both bleeding and death.

And in Caucasians, a different variant was linked to additional heart attacks and a higher risk of death.

The variations influence the way patients metabolize clopidogrel and can alter its effectiveness.

These findings were published in Circulation: Cardiovascular Genetics.

“The research is provocative,” said the study’s first author Sharon Cresci, MD, of the Washington University School of Medicine in St Louis.

“Knowing about potential genetic differences based on race can help physicians tailor drugs to patients based on their genetic makeup.”

Clopidogrel is metabolized in the liver, where it is turned into its active form via a group of enzymes called cytochrome P450 (CYP). Although clopidogrel is effective in many patients, earlier studies showed that some patients metabolize the drug better than others.

Indeed, in 2010, the US Food and Drug Administration added a black box warning to labels of clopidogrel after research (which primarily involved Caucasians) showed that people with a particular CYP genetic variant metabolized the drug poorly, which reduced the amount of the drug circulating in the blood. These patients had a higher risk of heart attack and stroke.

Additional studies showed that other CYP gene variants are linked to the rapid metabolism of clopidogrel, and patients with those variants had a higher risk of bleeding. But it has not been clear, until now, that the effects of these particular gene variations can vary by race.

To uncover this finding, Dr Cresci and her colleagues analyzed CYP variants among 2062 Caucasians and 670 African Americans who suffered heart attacks. Nearly 80% of the Caucasians and 65% of the African Americans were prescribed clopidogrel.

The patients were enrolled in a major study known as TRIUMPH (Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health), which was conducted from 2005 to 2008 at 24 US hospitals.

Among patients taking clopidogrel, the 1-year mortality rate for African Americans was 7.2%, compared with 3.6% for Caucasians.

Caucasians who carried the CYP2C19*2 variant, which has been linked to poor metabolism of the drug, had a higher rate of repeat heart attacks and death. However, among African Americans treated with clopidogrel, the CYP2C19*2 variant was not associated with a higher rate of death.

African Americans had higher rates of bleeding and death if they carried either of 2 other variants: CYP1A2*1C or CYP2C19*17, the latter of which has been associated with the rapid metabolism of clopidogrel. Among Caucasians on clopidogrel, neither variant increased the risk of death.

“This is very novel information that begs for more research,” said study author Richard G. Bach, MD, also of Washington University.

Although genetic testing is available to identify CYP variants in a patient’s DNA, these tests are not widely used by cardiologists. Results of the current study suggest this practice may need to be reconsidered.

“This research is an important addition to the field because previous studies looking at CYP gene variants and their effects on risks of repeat heart attacks, bleeding, and death have included predominantly Caucasian patients of European ancestry,” Dr Cresci noted. “There is almost no data, until now, about these variants in African Americans.”

Research examining how genetic variants alter the effectiveness of clopidogrel remains somewhat controversial, Dr Bach said. Many physicians feel that before they can tailor therapy for heart attack patients, more data is needed to prove a clear link between genetic variants and negative health consequences and that tailoring therapy will improve patients’ outcomes, he explained.

His hope is that additional research would provide more definitive conclusions to help physicians choose the best medications for patients after a heart attack and, ultimately, “to reduce the too-high rate of death and disability for patients after a heart attack,” Dr Bach said.

Dr Cresci agreed, adding, “By focusing on genetic differences, we may be able to individualize therapies after heart attacks and achieve the best treatment for each patient.”

Investigators Grace Liu

and Ross Dickins, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.

Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.

Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.

“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”

The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.

“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”

The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.

Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.

“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.

“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”

Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.

“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”

Investigators Grace Liu

and Ross Dickins, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.

Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.

Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.

“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”

The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.

“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”

The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.

Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.

“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.

“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”

Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.

“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”

Investigators Grace Liu

and Ross Dickins, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.

Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.

Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.

“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”

The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.

“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”

The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.

Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.

“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.

“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”

Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.

“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”

Doctor examining child

Credit: Logan Tuttle

MILAN—Eltrombopag can elicit consistent platelet responses in children with immune thrombocytopenia (ITP), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Results of the phase 3 PETIT2 study showed that eltrombopag can significantly improve platelet counts in pediatric ITP patients, when compared to placebo.

In fact, the drug enabled 61% of children to stop taking or reduce the dose of their other ITP medication.

John D. Grainger, MD, of the Royal Manchester Children’s Hospital in the UK, reported these results at the EHA Congress as abstract S732. The research was sponsored by GlaxoSmithKline, the makers of eltrombopag.

The PETIT2 trial, the largest study to date of pediatric patients with ITP, was conducted to establish eltrombopag’s efficacy, safety, and tolerability in children. The drug is not yet approved anywhere in the world for use in children.

The study included 92 children from 38 centers in 14 countries. All patients were 18 years old or younger, had chronic ITP for at least 12 months, had platelet counts less than 30 Gi/L, and had failed at least 1 prior treatment.

The researchers conducted the trial in 2 parts. The first lasted 13 weeks and randomized participants to receive either eltrombopag or placebo. The second phase lasted through week 24, and all participants received eltrombopag.

The primary endpoint was an increase in platelet count to 50 Gi/L or more. And eltrombopag met this endpoint, with a statistically significant improvement in platelet counts.

Almost 40% of patients maintained a consistent platelet count for 6 of 8 weeks, compared to 3% of patients who received placebo (P<0.001).

Fifty percent of eltrombopag-treated patients experienced reduced bleeding by week 12, and 66% did so by the end of the study.

Sixty-one percent of eltrombopag-treated patients were able to stop or reduce the other ITP medications they were taking.

These results were consistent across the ages enrolled.

The investigators did not observe any new safety concerns related to eltrombopag. The most common adverse events, which occurred more frequently in the eltrombopag-treated patients, were nasopharyngitis, rhinitis, cough, and respiratory tract infection.

Almost 13% of the eltrombopag-treated patients and 10% of the placebo-treated patients experienced grade 3/4 adverse events. Eight percent of eltrombopag-treated patients and 14% of placebo-treated patients had serious adverse events.

Four children discontinued the study due to a lack of response, and 5 children had abnormal liver tests that returned to normal after stopping the drug.

Given these results, the investigators concluded that eltrombopag has the potential to treat childhood ITP.

Eltrombopag is marketed as Promacta in the United States and Revolade in the European Union.

Doctor examining child

Credit: Logan Tuttle

MILAN—Eltrombopag can elicit consistent platelet responses in children with immune thrombocytopenia (ITP), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Results of the phase 3 PETIT2 study showed that eltrombopag can significantly improve platelet counts in pediatric ITP patients, when compared to placebo.

In fact, the drug enabled 61% of children to stop taking or reduce the dose of their other ITP medication.

John D. Grainger, MD, of the Royal Manchester Children’s Hospital in the UK, reported these results at the EHA Congress as abstract S732. The research was sponsored by GlaxoSmithKline, the makers of eltrombopag.

The PETIT2 trial, the largest study to date of pediatric patients with ITP, was conducted to establish eltrombopag’s efficacy, safety, and tolerability in children. The drug is not yet approved anywhere in the world for use in children.

The study included 92 children from 38 centers in 14 countries. All patients were 18 years old or younger, had chronic ITP for at least 12 months, had platelet counts less than 30 Gi/L, and had failed at least 1 prior treatment.

The researchers conducted the trial in 2 parts. The first lasted 13 weeks and randomized participants to receive either eltrombopag or placebo. The second phase lasted through week 24, and all participants received eltrombopag.

The primary endpoint was an increase in platelet count to 50 Gi/L or more. And eltrombopag met this endpoint, with a statistically significant improvement in platelet counts.

Almost 40% of patients maintained a consistent platelet count for 6 of 8 weeks, compared to 3% of patients who received placebo (P<0.001).

Fifty percent of eltrombopag-treated patients experienced reduced bleeding by week 12, and 66% did so by the end of the study.

Sixty-one percent of eltrombopag-treated patients were able to stop or reduce the other ITP medications they were taking.

These results were consistent across the ages enrolled.

The investigators did not observe any new safety concerns related to eltrombopag. The most common adverse events, which occurred more frequently in the eltrombopag-treated patients, were nasopharyngitis, rhinitis, cough, and respiratory tract infection.

Almost 13% of the eltrombopag-treated patients and 10% of the placebo-treated patients experienced grade 3/4 adverse events. Eight percent of eltrombopag-treated patients and 14% of placebo-treated patients had serious adverse events.

Four children discontinued the study due to a lack of response, and 5 children had abnormal liver tests that returned to normal after stopping the drug.

Given these results, the investigators concluded that eltrombopag has the potential to treat childhood ITP.

Eltrombopag is marketed as Promacta in the United States and Revolade in the European Union.

Doctor examining child

Credit: Logan Tuttle

MILAN—Eltrombopag can elicit consistent platelet responses in children with immune thrombocytopenia (ITP), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Results of the phase 3 PETIT2 study showed that eltrombopag can significantly improve platelet counts in pediatric ITP patients, when compared to placebo.

In fact, the drug enabled 61% of children to stop taking or reduce the dose of their other ITP medication.

John D. Grainger, MD, of the Royal Manchester Children’s Hospital in the UK, reported these results at the EHA Congress as abstract S732. The research was sponsored by GlaxoSmithKline, the makers of eltrombopag.

The PETIT2 trial, the largest study to date of pediatric patients with ITP, was conducted to establish eltrombopag’s efficacy, safety, and tolerability in children. The drug is not yet approved anywhere in the world for use in children.

The study included 92 children from 38 centers in 14 countries. All patients were 18 years old or younger, had chronic ITP for at least 12 months, had platelet counts less than 30 Gi/L, and had failed at least 1 prior treatment.

The researchers conducted the trial in 2 parts. The first lasted 13 weeks and randomized participants to receive either eltrombopag or placebo. The second phase lasted through week 24, and all participants received eltrombopag.

The primary endpoint was an increase in platelet count to 50 Gi/L or more. And eltrombopag met this endpoint, with a statistically significant improvement in platelet counts.

Almost 40% of patients maintained a consistent platelet count for 6 of 8 weeks, compared to 3% of patients who received placebo (P<0.001).

Fifty percent of eltrombopag-treated patients experienced reduced bleeding by week 12, and 66% did so by the end of the study.

Sixty-one percent of eltrombopag-treated patients were able to stop or reduce the other ITP medications they were taking.

These results were consistent across the ages enrolled.

The investigators did not observe any new safety concerns related to eltrombopag. The most common adverse events, which occurred more frequently in the eltrombopag-treated patients, were nasopharyngitis, rhinitis, cough, and respiratory tract infection.

Almost 13% of the eltrombopag-treated patients and 10% of the placebo-treated patients experienced grade 3/4 adverse events. Eight percent of eltrombopag-treated patients and 14% of placebo-treated patients had serious adverse events.

Four children discontinued the study due to a lack of response, and 5 children had abnormal liver tests that returned to normal after stopping the drug.

Given these results, the investigators concluded that eltrombopag has the potential to treat childhood ITP.

Eltrombopag is marketed as Promacta in the United States and Revolade in the European Union.

Thrombus

Credit: Andre E.X. Brown

Results of a large analysis indicate that adding thrombolytics to conventional anticoagulant therapy can lower the rates of death and recurrence in patients with pulmonary embolism (PE).

But the practice can also increase the risk of major bleeding and intracranial hemorrhage.

Saurav Chatterjee, MD, of St Luke’s-Roosevelt Hospital Center of the Mount Sinai Health System in New York, and his colleagues described these findings in JAMA.

The team performed a meta-analysis of 16 randomized, clinical trials of patients with PE (n=2115).

Roughly half of the patients received both thrombolytic therapy (drugs such as alteplase and tenecteplase) and conventional anticoagulation therapy (drugs such as heparin), and the other half received only conventional anticoagulation treatment.

Using criteria such as low blood pressure, heart damage revealed by diagnostic testing, and shortness of breath, physicians classified patients as being at high-risk, intermediate-risk, and low-risk of dying from PE.

Seventy-one percent of the studied patients had intermediate-risk PE, 9.9% had low-risk PE, and 1.5% had high-risk PE. Risk could not be classified in 18% of patients.

In all risk groups combined, thrombolytic therapy lowered the risk of recurrent PE when compared to anticoagulant therapy alone. The incidence of recurrent PE was 1.2% and 3%, respectively.

In addition, thrombolytic therapy was associated with a 47% decreased risk of death. There was a 2.2% incidence of mortality among patients who received thrombolytics and a 3.9% incidence among patients who received anticoagulants alone.

On the other hand, thrombolytic therapy was associated with a 2.7-times greater risk of major bleeding when compared to anticoagulants alone.

There was a 9.2% incidence of major bleeding in the thrombolytic group and a 3.4% incidence in the anticoagulant-only group. However, major bleeding was not significantly increased in patients 65 years of age and younger.

Thrombolytic therapy was also associated with a higher incidence of intracranial hemorrhage when compared to anticoagulant therapy alone, with rates of 1.5% and 0.2%, respectively.

“With this knowledge, future research can help identify subgroups of patients who are most likely to obtain [the] mortality benefit [of thrombolytic therapy] and least likely to be harmed by bleeding, particularly intracranial hemorrhage,” said study author Jay Giri, MD, MPH, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

“Research should focus on standardization of dosages of medication in thrombolysis, as well as explore the optimal method of administration—namely, intravenous vs catheter-directed therapy into the pulmonary arteries—to determine maximal clinical benefits with minimization of bleeding risk.”

Thrombus

Credit: Andre E.X. Brown

Results of a large analysis indicate that adding thrombolytics to conventional anticoagulant therapy can lower the rates of death and recurrence in patients with pulmonary embolism (PE).

But the practice can also increase the risk of major bleeding and intracranial hemorrhage.

Saurav Chatterjee, MD, of St Luke’s-Roosevelt Hospital Center of the Mount Sinai Health System in New York, and his colleagues described these findings in JAMA.

The team performed a meta-analysis of 16 randomized, clinical trials of patients with PE (n=2115).

Roughly half of the patients received both thrombolytic therapy (drugs such as alteplase and tenecteplase) and conventional anticoagulation therapy (drugs such as heparin), and the other half received only conventional anticoagulation treatment.

Using criteria such as low blood pressure, heart damage revealed by diagnostic testing, and shortness of breath, physicians classified patients as being at high-risk, intermediate-risk, and low-risk of dying from PE.

Seventy-one percent of the studied patients had intermediate-risk PE, 9.9% had low-risk PE, and 1.5% had high-risk PE. Risk could not be classified in 18% of patients.

In all risk groups combined, thrombolytic therapy lowered the risk of recurrent PE when compared to anticoagulant therapy alone. The incidence of recurrent PE was 1.2% and 3%, respectively.

In addition, thrombolytic therapy was associated with a 47% decreased risk of death. There was a 2.2% incidence of mortality among patients who received thrombolytics and a 3.9% incidence among patients who received anticoagulants alone.

On the other hand, thrombolytic therapy was associated with a 2.7-times greater risk of major bleeding when compared to anticoagulants alone.

There was a 9.2% incidence of major bleeding in the thrombolytic group and a 3.4% incidence in the anticoagulant-only group. However, major bleeding was not significantly increased in patients 65 years of age and younger.

Thrombolytic therapy was also associated with a higher incidence of intracranial hemorrhage when compared to anticoagulant therapy alone, with rates of 1.5% and 0.2%, respectively.

“With this knowledge, future research can help identify subgroups of patients who are most likely to obtain [the] mortality benefit [of thrombolytic therapy] and least likely to be harmed by bleeding, particularly intracranial hemorrhage,” said study author Jay Giri, MD, MPH, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

“Research should focus on standardization of dosages of medication in thrombolysis, as well as explore the optimal method of administration—namely, intravenous vs catheter-directed therapy into the pulmonary arteries—to determine maximal clinical benefits with minimization of bleeding risk.”

Thrombus

Credit: Andre E.X. Brown

Results of a large analysis indicate that adding thrombolytics to conventional anticoagulant therapy can lower the rates of death and recurrence in patients with pulmonary embolism (PE).

But the practice can also increase the risk of major bleeding and intracranial hemorrhage.

Saurav Chatterjee, MD, of St Luke’s-Roosevelt Hospital Center of the Mount Sinai Health System in New York, and his colleagues described these findings in JAMA.

The team performed a meta-analysis of 16 randomized, clinical trials of patients with PE (n=2115).

Roughly half of the patients received both thrombolytic therapy (drugs such as alteplase and tenecteplase) and conventional anticoagulation therapy (drugs such as heparin), and the other half received only conventional anticoagulation treatment.

Using criteria such as low blood pressure, heart damage revealed by diagnostic testing, and shortness of breath, physicians classified patients as being at high-risk, intermediate-risk, and low-risk of dying from PE.

Seventy-one percent of the studied patients had intermediate-risk PE, 9.9% had low-risk PE, and 1.5% had high-risk PE. Risk could not be classified in 18% of patients.

In all risk groups combined, thrombolytic therapy lowered the risk of recurrent PE when compared to anticoagulant therapy alone. The incidence of recurrent PE was 1.2% and 3%, respectively.

In addition, thrombolytic therapy was associated with a 47% decreased risk of death. There was a 2.2% incidence of mortality among patients who received thrombolytics and a 3.9% incidence among patients who received anticoagulants alone.

On the other hand, thrombolytic therapy was associated with a 2.7-times greater risk of major bleeding when compared to anticoagulants alone.

There was a 9.2% incidence of major bleeding in the thrombolytic group and a 3.4% incidence in the anticoagulant-only group. However, major bleeding was not significantly increased in patients 65 years of age and younger.

Thrombolytic therapy was also associated with a higher incidence of intracranial hemorrhage when compared to anticoagulant therapy alone, with rates of 1.5% and 0.2%, respectively.

“With this knowledge, future research can help identify subgroups of patients who are most likely to obtain [the] mortality benefit [of thrombolytic therapy] and least likely to be harmed by bleeding, particularly intracranial hemorrhage,” said study author Jay Giri, MD, MPH, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

“Research should focus on standardization of dosages of medication in thrombolysis, as well as explore the optimal method of administration—namely, intravenous vs catheter-directed therapy into the pulmonary arteries—to determine maximal clinical benefits with minimization of bleeding risk.”

Lab mice

Credit: Aaron Logan

Researchers say they’ve uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain.

The team believes the findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the central nervous system (CNS).

Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth.

But these therapies can cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” said study author Cynthia Guidos, PhD, of The Hospital for Sick Children (SickKids) in Toronto, Canada.

“Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS and may be less toxic than current treatments.”

Using a mouse model, the researchers found that CNS-invading leukemias expressed higher levels of Flt3 than leukemias that did not spread to the CNS.

And the CNS-invading leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain. And this endowed them with the ability to spread to the CNS.

The team also showed that a Flt3 inhibitor halted growth of the CNS leukemia cells in vitro.

Dr Guidos said the next step for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL.

She and her colleagues plan to use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from more than 100 patients, to do just that.

Lab mice

Credit: Aaron Logan

Researchers say they’ve uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain.

The team believes the findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the central nervous system (CNS).

Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth.

But these therapies can cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” said study author Cynthia Guidos, PhD, of The Hospital for Sick Children (SickKids) in Toronto, Canada.

“Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS and may be less toxic than current treatments.”

Using a mouse model, the researchers found that CNS-invading leukemias expressed higher levels of Flt3 than leukemias that did not spread to the CNS.

And the CNS-invading leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain. And this endowed them with the ability to spread to the CNS.

The team also showed that a Flt3 inhibitor halted growth of the CNS leukemia cells in vitro.

Dr Guidos said the next step for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL.

She and her colleagues plan to use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from more than 100 patients, to do just that.

Lab mice

Credit: Aaron Logan

Researchers say they’ve uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain.

The team believes the findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the central nervous system (CNS).

Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth.

But these therapies can cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” said study author Cynthia Guidos, PhD, of The Hospital for Sick Children (SickKids) in Toronto, Canada.

“Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS and may be less toxic than current treatments.”

Using a mouse model, the researchers found that CNS-invading leukemias expressed higher levels of Flt3 than leukemias that did not spread to the CNS.

And the CNS-invading leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain. And this endowed them with the ability to spread to the CNS.

The team also showed that a Flt3 inhibitor halted growth of the CNS leukemia cells in vitro.

Dr Guidos said the next step for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL.

She and her colleagues plan to use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from more than 100 patients, to do just that.

Gut bacteria

The diversity of gut microbiota in patients receiving allogeneic stem cell transplants (allo-SCTs) may be an important predictor of their survival, according to a study published in Blood.

Previous studies have suggested the intensive treatment given to allo-SCT recipients can destroy a significant portion of their gut microbiota and reduce its overall diversity.

And disturbances of the gut microbiota have been associated with complications such as bloodstream infections and graft-vs-host disease.

“While the link between gut microbiota and complications in allogeneic SCT has been previously established, until this point, it has remained unclear whether the gut bacteria of transplant recipients could predict their survival,” said study author Ying Taur, MD, of Memorial Sloan-Kettering Cancer Center in New York.

“This study sought to further explore the potential connection between transplantation, gut bacteria, and overall survival.”

To that end, the researchers collected fecal specimens from 80 patients undergoing allo-SCT and sequenced each sample’s bacterial DNA. Specimens were collected within 7 days of engraftment, the point at which the researchers speculated that microbiota diversity would be greatest following pre-transplant conditioning.

The team compared patient outcomes based on diversity of microbiota in their specimens, grouping subjects into high-, intermediate-, and low-microbiota-diversity categories.

At engraftment, 34 patients (42.5%) had low diversity, 20 (25%) had intermediate diversity, and 26 (32.5%) had high diversity. The analysis continued for up to 3 years or until death or last follow-up.

Following their analyses, the researchers found a strong connection between post-transplant gut microbiota diversity and outcomes, observing overall survival rates of 36%, 60%, and 67% among the low-, intermediate-, and high-diversity groups, respectively.

Furthermore, diversity was particularly associated with transplant-related outcomes. Patients with low microbiota diversity were approximately 5 times more likely to die of transplant-related causes within the follow-up period than those with more diverse gut bacteria.

“These results further underscore the significance of the gut microbiota in allogeneic stem cell transplant,” Dr Taur said. “A major question is whether we can improve outcomes by preserving diversity within the gut microbiota.”

“One possible strategy is to find ways to perform transplants in a manner that minimizes damage to the gut microbiota. Another approach would be to replenish the gut with beneficial microbes that are lost after this procedure is performed. We hope that this study will inspire additional research that will further examine the role and importance of the gut microbiota to stem cell transplant outcome.”

Gut bacteria

The diversity of gut microbiota in patients receiving allogeneic stem cell transplants (allo-SCTs) may be an important predictor of their survival, according to a study published in Blood.

Previous studies have suggested the intensive treatment given to allo-SCT recipients can destroy a significant portion of their gut microbiota and reduce its overall diversity.

And disturbances of the gut microbiota have been associated with complications such as bloodstream infections and graft-vs-host disease.

“While the link between gut microbiota and complications in allogeneic SCT has been previously established, until this point, it has remained unclear whether the gut bacteria of transplant recipients could predict their survival,” said study author Ying Taur, MD, of Memorial Sloan-Kettering Cancer Center in New York.

“This study sought to further explore the potential connection between transplantation, gut bacteria, and overall survival.”

To that end, the researchers collected fecal specimens from 80 patients undergoing allo-SCT and sequenced each sample’s bacterial DNA. Specimens were collected within 7 days of engraftment, the point at which the researchers speculated that microbiota diversity would be greatest following pre-transplant conditioning.

The team compared patient outcomes based on diversity of microbiota in their specimens, grouping subjects into high-, intermediate-, and low-microbiota-diversity categories.

At engraftment, 34 patients (42.5%) had low diversity, 20 (25%) had intermediate diversity, and 26 (32.5%) had high diversity. The analysis continued for up to 3 years or until death or last follow-up.

Following their analyses, the researchers found a strong connection between post-transplant gut microbiota diversity and outcomes, observing overall survival rates of 36%, 60%, and 67% among the low-, intermediate-, and high-diversity groups, respectively.

Furthermore, diversity was particularly associated with transplant-related outcomes. Patients with low microbiota diversity were approximately 5 times more likely to die of transplant-related causes within the follow-up period than those with more diverse gut bacteria.

“These results further underscore the significance of the gut microbiota in allogeneic stem cell transplant,” Dr Taur said. “A major question is whether we can improve outcomes by preserving diversity within the gut microbiota.”

“One possible strategy is to find ways to perform transplants in a manner that minimizes damage to the gut microbiota. Another approach would be to replenish the gut with beneficial microbes that are lost after this procedure is performed. We hope that this study will inspire additional research that will further examine the role and importance of the gut microbiota to stem cell transplant outcome.”

Gut bacteria

The diversity of gut microbiota in patients receiving allogeneic stem cell transplants (allo-SCTs) may be an important predictor of their survival, according to a study published in Blood.

Previous studies have suggested the intensive treatment given to allo-SCT recipients can destroy a significant portion of their gut microbiota and reduce its overall diversity.

And disturbances of the gut microbiota have been associated with complications such as bloodstream infections and graft-vs-host disease.

“While the link between gut microbiota and complications in allogeneic SCT has been previously established, until this point, it has remained unclear whether the gut bacteria of transplant recipients could predict their survival,” said study author Ying Taur, MD, of Memorial Sloan-Kettering Cancer Center in New York.

“This study sought to further explore the potential connection between transplantation, gut bacteria, and overall survival.”

To that end, the researchers collected fecal specimens from 80 patients undergoing allo-SCT and sequenced each sample’s bacterial DNA. Specimens were collected within 7 days of engraftment, the point at which the researchers speculated that microbiota diversity would be greatest following pre-transplant conditioning.

The team compared patient outcomes based on diversity of microbiota in their specimens, grouping subjects into high-, intermediate-, and low-microbiota-diversity categories.

At engraftment, 34 patients (42.5%) had low diversity, 20 (25%) had intermediate diversity, and 26 (32.5%) had high diversity. The analysis continued for up to 3 years or until death or last follow-up.

Following their analyses, the researchers found a strong connection between post-transplant gut microbiota diversity and outcomes, observing overall survival rates of 36%, 60%, and 67% among the low-, intermediate-, and high-diversity groups, respectively.

Furthermore, diversity was particularly associated with transplant-related outcomes. Patients with low microbiota diversity were approximately 5 times more likely to die of transplant-related causes within the follow-up period than those with more diverse gut bacteria.

“These results further underscore the significance of the gut microbiota in allogeneic stem cell transplant,” Dr Taur said. “A major question is whether we can improve outcomes by preserving diversity within the gut microbiota.”

“One possible strategy is to find ways to perform transplants in a manner that minimizes damage to the gut microbiota. Another approach would be to replenish the gut with beneficial microbes that are lost after this procedure is performed. We hope that this study will inspire additional research that will further examine the role and importance of the gut microbiota to stem cell transplant outcome.”