Hematology Times

Monocyte

Image by Bruce Blaus

Cells associated with inflammation and coagulation accumulate in the brains of children with cerebral malaria (CM), according to research published in mBio.

The researchers studied autopsied brain tissue from more than 100 African children and found that children with CM had a more than 9-fold greater number of intravascular monocytes and platelets than children who did not have malaria.

In addition, HIV-positive children had more than twice the amount of intravascular monocytes and platelets than was observed in children who were not HIV-positive.

“Our study clearly shows that HIV exacerbates the disease process in cerebral malaria and also leads to some really interesting insights into what may be going on with children who are dying of cerebral malaria, which has been very controversial,” said study author Kami Kim, MD, of the Albert Einstein College of Medicine in the Bronx, New York.

“Children who are HIV-positive and at risk for malaria may benefit from targeted antimalaria drugs, and adjunctive therapies that target inflammation or blood clotting may improve outcomes from CM.”

CM is one of the most severe complications of malaria and can lead to behavioral problems, seizures, coma, or death. It is mainly seen in children younger than 5 living in sub-Saharan Africa.

CM is fairly rare, affecting about 2% of children with malaria, but CM is also thought to be responsible for half of malaria deaths.

“So it’s a big deal,” Dr Kim said. “The more we know about CM, the more that we can theoretically do something either to better treat or prevent it.”

With this goal in mind, Dr Kim and her colleagues analyzed children in an ongoing study of pediatric CM in Blantyre, Malawi. The researchers enrolled more than 3000 participants and completed 103 autopsies in those who died from either CM or other causes of coma.

HIV prevalence was higher than expected and led to higher mortality in CM patients. The prevalence of HIV was 14.5% in children enrolled in the study, compared to 2% in the general Malawi pediatric population.

Twenty-three percent of HIV-positive children died, while 17% of those without HIV died. Twenty percent of autopsy cases were HIV-positive.

The researchers noted that HIV-infected children with CM were older than children without HIV (an average of 99 months vs 32 months) and were not severely immunocompromised.

In addition, monocytes and platelets were significantly more prevalent in HIV-positive children with CM than neutrophils.

“We identified a unique and pervasive pathology pattern in pediatric CM, marked by monocytes and platelets, which is more severe in HIV-positive children,” Dr Kim said.

“It doesn’t prove that these cells cause clinical disease, but the fact that they’re there in huge abundance when there’s a lot of parasites is pretty strongly suggestive evidence that they’re doing something. We never see that in healthy brain tissue.”

Additional studies of children with varying severities of malaria are necessary in order to design better treatment algorithms, Dr Kim added.

Monocyte

Image by Bruce Blaus

Cells associated with inflammation and coagulation accumulate in the brains of children with cerebral malaria (CM), according to research published in mBio.

The researchers studied autopsied brain tissue from more than 100 African children and found that children with CM had a more than 9-fold greater number of intravascular monocytes and platelets than children who did not have malaria.

In addition, HIV-positive children had more than twice the amount of intravascular monocytes and platelets than was observed in children who were not HIV-positive.

“Our study clearly shows that HIV exacerbates the disease process in cerebral malaria and also leads to some really interesting insights into what may be going on with children who are dying of cerebral malaria, which has been very controversial,” said study author Kami Kim, MD, of the Albert Einstein College of Medicine in the Bronx, New York.

“Children who are HIV-positive and at risk for malaria may benefit from targeted antimalaria drugs, and adjunctive therapies that target inflammation or blood clotting may improve outcomes from CM.”

CM is one of the most severe complications of malaria and can lead to behavioral problems, seizures, coma, or death. It is mainly seen in children younger than 5 living in sub-Saharan Africa.

CM is fairly rare, affecting about 2% of children with malaria, but CM is also thought to be responsible for half of malaria deaths.

“So it’s a big deal,” Dr Kim said. “The more we know about CM, the more that we can theoretically do something either to better treat or prevent it.”

With this goal in mind, Dr Kim and her colleagues analyzed children in an ongoing study of pediatric CM in Blantyre, Malawi. The researchers enrolled more than 3000 participants and completed 103 autopsies in those who died from either CM or other causes of coma.

HIV prevalence was higher than expected and led to higher mortality in CM patients. The prevalence of HIV was 14.5% in children enrolled in the study, compared to 2% in the general Malawi pediatric population.

Twenty-three percent of HIV-positive children died, while 17% of those without HIV died. Twenty percent of autopsy cases were HIV-positive.

The researchers noted that HIV-infected children with CM were older than children without HIV (an average of 99 months vs 32 months) and were not severely immunocompromised.

In addition, monocytes and platelets were significantly more prevalent in HIV-positive children with CM than neutrophils.

“We identified a unique and pervasive pathology pattern in pediatric CM, marked by monocytes and platelets, which is more severe in HIV-positive children,” Dr Kim said.

“It doesn’t prove that these cells cause clinical disease, but the fact that they’re there in huge abundance when there’s a lot of parasites is pretty strongly suggestive evidence that they’re doing something. We never see that in healthy brain tissue.”

Additional studies of children with varying severities of malaria are necessary in order to design better treatment algorithms, Dr Kim added.

Monocyte

Image by Bruce Blaus

Cells associated with inflammation and coagulation accumulate in the brains of children with cerebral malaria (CM), according to research published in mBio.

The researchers studied autopsied brain tissue from more than 100 African children and found that children with CM had a more than 9-fold greater number of intravascular monocytes and platelets than children who did not have malaria.

In addition, HIV-positive children had more than twice the amount of intravascular monocytes and platelets than was observed in children who were not HIV-positive.

“Our study clearly shows that HIV exacerbates the disease process in cerebral malaria and also leads to some really interesting insights into what may be going on with children who are dying of cerebral malaria, which has been very controversial,” said study author Kami Kim, MD, of the Albert Einstein College of Medicine in the Bronx, New York.

“Children who are HIV-positive and at risk for malaria may benefit from targeted antimalaria drugs, and adjunctive therapies that target inflammation or blood clotting may improve outcomes from CM.”

CM is one of the most severe complications of malaria and can lead to behavioral problems, seizures, coma, or death. It is mainly seen in children younger than 5 living in sub-Saharan Africa.

CM is fairly rare, affecting about 2% of children with malaria, but CM is also thought to be responsible for half of malaria deaths.

“So it’s a big deal,” Dr Kim said. “The more we know about CM, the more that we can theoretically do something either to better treat or prevent it.”

With this goal in mind, Dr Kim and her colleagues analyzed children in an ongoing study of pediatric CM in Blantyre, Malawi. The researchers enrolled more than 3000 participants and completed 103 autopsies in those who died from either CM or other causes of coma.

HIV prevalence was higher than expected and led to higher mortality in CM patients. The prevalence of HIV was 14.5% in children enrolled in the study, compared to 2% in the general Malawi pediatric population.

Twenty-three percent of HIV-positive children died, while 17% of those without HIV died. Twenty percent of autopsy cases were HIV-positive.

The researchers noted that HIV-infected children with CM were older than children without HIV (an average of 99 months vs 32 months) and were not severely immunocompromised.

In addition, monocytes and platelets were significantly more prevalent in HIV-positive children with CM than neutrophils.

“We identified a unique and pervasive pathology pattern in pediatric CM, marked by monocytes and platelets, which is more severe in HIV-positive children,” Dr Kim said.

“It doesn’t prove that these cells cause clinical disease, but the fact that they’re there in huge abundance when there’s a lot of parasites is pretty strongly suggestive evidence that they’re doing something. We never see that in healthy brain tissue.”

Additional studies of children with varying severities of malaria are necessary in order to design better treatment algorithms, Dr Kim added.

Patient receiving chemotherapy

Photo by Rhoda Baer

SAN DIEGO—Monitoring the microbiome during chemotherapy might help reduce infections in leukemia patients, according to research presented at ICAAC/ICC 2015.

The researchers studied buccal and fecal samples from patients with acute myeloid leukemia (AML) who were undergoing induction chemotherapy.

This revealed that decreased microbial diversity was associated with an increased risk of infection.

Jessica Galloway-Peña, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues described this work in a poster presentation at the meeting (poster B-993).

The team analyzed samples from 34 AML patients. All of the patients received prophylactic antimicrobials, and 91% received systemic antibiotics. The patients received an average of 5.4 different antibiotics for an average duration of 6.5 days.

The researchers collected buccal and fecal specimens from the patients every 96 hours over the course of induction chemotherapy. This yielded 276 buccal and 202 fecal samples—an average of 8 oral and 6 stool samples per patient.

The team used 16S rRNA V4 region sequencing to assign bacterial taxa and calculate α- and β-diversities. They had a total of 16,082,550 high-quality reads.

Analyzing these data, the researchers found that decreased microbial diversity, both at baseline and throughout induction, was associated with an increased risk of infection.

“We found the baseline microbial diversities from stool samples were significantly lower in patients that developed infections during chemotherapy compared to those that did not [P=0.006],” Dr Galloway-Peña said.

She and her colleagues also found that, overall, there was a significant decrease in oral (P=0.006) and intestinal (P<0.001) microbial diversity over the course of chemotherapy, although not all patients experienced decreases. There was a linear correlation between oral and stool microbiome changes (P=0.004).

In addition, over the course of induction, there was a significant increase (P=0.02) in the rates of bacterial domination (>30% of the microbiome dominated by 1 organism) by common causes of bacteremia, such as Streptococcus, Bacteriodes, Rothia, and Staphylococcus.

However, if patients were able to maintain a healthy microbiome overall or if they experienced an increase in microbial diversity over the induction course, they remained infection-free in the 90 days after induction.

Dr Galloway-Peña and her colleagues also assessed the role common antibiotics play in microbial diversity. And they found that carbapenems significantly decreased diversity.

There was a significant difference in oral and stool diversity when patients received carbapenems for at least 72 hours and when they did not (P=0.03). But there was no significant difference for piperacillin-tazobactam (P=1.0) or cefepime (P=0.48).

“This study shows that, in the future, doctors could use microbiome sampling in order to predict the chance of infectious complications during chemotherapy and that monitoring of a patient’s microbiome during induction chemotherapy could also predict their risk for microbial-related illness during subsequent treatments,” Dr Galloway-Peña said.

In addition, monitoring the microbiome could potentially mitigate the overuse of antimicrobials by allowing physicians to stratify patients according to their risk of developing an infection.

Patient receiving chemotherapy

Photo by Rhoda Baer

SAN DIEGO—Monitoring the microbiome during chemotherapy might help reduce infections in leukemia patients, according to research presented at ICAAC/ICC 2015.

The researchers studied buccal and fecal samples from patients with acute myeloid leukemia (AML) who were undergoing induction chemotherapy.

This revealed that decreased microbial diversity was associated with an increased risk of infection.

Jessica Galloway-Peña, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues described this work in a poster presentation at the meeting (poster B-993).

The team analyzed samples from 34 AML patients. All of the patients received prophylactic antimicrobials, and 91% received systemic antibiotics. The patients received an average of 5.4 different antibiotics for an average duration of 6.5 days.

The researchers collected buccal and fecal specimens from the patients every 96 hours over the course of induction chemotherapy. This yielded 276 buccal and 202 fecal samples—an average of 8 oral and 6 stool samples per patient.

The team used 16S rRNA V4 region sequencing to assign bacterial taxa and calculate α- and β-diversities. They had a total of 16,082,550 high-quality reads.

Analyzing these data, the researchers found that decreased microbial diversity, both at baseline and throughout induction, was associated with an increased risk of infection.

“We found the baseline microbial diversities from stool samples were significantly lower in patients that developed infections during chemotherapy compared to those that did not [P=0.006],” Dr Galloway-Peña said.

She and her colleagues also found that, overall, there was a significant decrease in oral (P=0.006) and intestinal (P<0.001) microbial diversity over the course of chemotherapy, although not all patients experienced decreases. There was a linear correlation between oral and stool microbiome changes (P=0.004).

In addition, over the course of induction, there was a significant increase (P=0.02) in the rates of bacterial domination (>30% of the microbiome dominated by 1 organism) by common causes of bacteremia, such as Streptococcus, Bacteriodes, Rothia, and Staphylococcus.

However, if patients were able to maintain a healthy microbiome overall or if they experienced an increase in microbial diversity over the induction course, they remained infection-free in the 90 days after induction.

Dr Galloway-Peña and her colleagues also assessed the role common antibiotics play in microbial diversity. And they found that carbapenems significantly decreased diversity.

There was a significant difference in oral and stool diversity when patients received carbapenems for at least 72 hours and when they did not (P=0.03). But there was no significant difference for piperacillin-tazobactam (P=1.0) or cefepime (P=0.48).

“This study shows that, in the future, doctors could use microbiome sampling in order to predict the chance of infectious complications during chemotherapy and that monitoring of a patient’s microbiome during induction chemotherapy could also predict their risk for microbial-related illness during subsequent treatments,” Dr Galloway-Peña said.

In addition, monitoring the microbiome could potentially mitigate the overuse of antimicrobials by allowing physicians to stratify patients according to their risk of developing an infection.

Patient receiving chemotherapy

Photo by Rhoda Baer

SAN DIEGO—Monitoring the microbiome during chemotherapy might help reduce infections in leukemia patients, according to research presented at ICAAC/ICC 2015.

The researchers studied buccal and fecal samples from patients with acute myeloid leukemia (AML) who were undergoing induction chemotherapy.

This revealed that decreased microbial diversity was associated with an increased risk of infection.

Jessica Galloway-Peña, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues described this work in a poster presentation at the meeting (poster B-993).

The team analyzed samples from 34 AML patients. All of the patients received prophylactic antimicrobials, and 91% received systemic antibiotics. The patients received an average of 5.4 different antibiotics for an average duration of 6.5 days.

The researchers collected buccal and fecal specimens from the patients every 96 hours over the course of induction chemotherapy. This yielded 276 buccal and 202 fecal samples—an average of 8 oral and 6 stool samples per patient.

The team used 16S rRNA V4 region sequencing to assign bacterial taxa and calculate α- and β-diversities. They had a total of 16,082,550 high-quality reads.

Analyzing these data, the researchers found that decreased microbial diversity, both at baseline and throughout induction, was associated with an increased risk of infection.

“We found the baseline microbial diversities from stool samples were significantly lower in patients that developed infections during chemotherapy compared to those that did not [P=0.006],” Dr Galloway-Peña said.

She and her colleagues also found that, overall, there was a significant decrease in oral (P=0.006) and intestinal (P<0.001) microbial diversity over the course of chemotherapy, although not all patients experienced decreases. There was a linear correlation between oral and stool microbiome changes (P=0.004).

In addition, over the course of induction, there was a significant increase (P=0.02) in the rates of bacterial domination (>30% of the microbiome dominated by 1 organism) by common causes of bacteremia, such as Streptococcus, Bacteriodes, Rothia, and Staphylococcus.

However, if patients were able to maintain a healthy microbiome overall or if they experienced an increase in microbial diversity over the induction course, they remained infection-free in the 90 days after induction.

Dr Galloway-Peña and her colleagues also assessed the role common antibiotics play in microbial diversity. And they found that carbapenems significantly decreased diversity.

There was a significant difference in oral and stool diversity when patients received carbapenems for at least 72 hours and when they did not (P=0.03). But there was no significant difference for piperacillin-tazobactam (P=1.0) or cefepime (P=0.48).

“This study shows that, in the future, doctors could use microbiome sampling in order to predict the chance of infectious complications during chemotherapy and that monitoring of a patient’s microbiome during induction chemotherapy could also predict their risk for microbial-related illness during subsequent treatments,” Dr Galloway-Peña said.

In addition, monitoring the microbiome could potentially mitigate the overuse of antimicrobials by allowing physicians to stratify patients according to their risk of developing an infection.

Carl June, MD

Photo courtesy of the

University of Pennsylvania

NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.

One thing investigators have determined is that persistence of the CARs is essential for long-term responses.

In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.

Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.

These results were recently published in Science Translational Medicine.

Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.

In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.

“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.

The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.

“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”

The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.

The investigators have not observed a CD19 loss in any CLL patient who responded.

“Patients who have gone into remission stay in remission,” Dr June added.

Kinetics of delayed CR

Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.

Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.

He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.

Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.

“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”

Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.

Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.

“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”

He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”

Carl June, MD

Photo courtesy of the

University of Pennsylvania

NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.

One thing investigators have determined is that persistence of the CARs is essential for long-term responses.

In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.

Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.

These results were recently published in Science Translational Medicine.

Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.

In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.

“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.

The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.

“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”

The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.

The investigators have not observed a CD19 loss in any CLL patient who responded.

“Patients who have gone into remission stay in remission,” Dr June added.

Kinetics of delayed CR

Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.

Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.

He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.

Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.

“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”

Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.

Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.

“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”

He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”

Carl June, MD

Photo courtesy of the

University of Pennsylvania

NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.

One thing investigators have determined is that persistence of the CARs is essential for long-term responses.

In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.

Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.

These results were recently published in Science Translational Medicine.

Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.

In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.

“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.

The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.

“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”

The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.

The investigators have not observed a CD19 loss in any CLL patient who responded.

“Patients who have gone into remission stay in remission,” Dr June added.

Kinetics of delayed CR

Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.

Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.

He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.

Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.

“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”

Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.

Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.

“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”

He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”

Malaria-infected cell bursting

Image by Peter H. Seeberger

Researchers say they have identified a mechanism of multidrug resistance in malaria that represents a major threat to antimalarial drug policy.

The team exposed a strain of malaria parasites to artemisinin (the base compound for standard therapy) long-term and found the parasites developed widespread resistance to most other antimalarial drugs.

The group also discovered that this type of resistance cannot be detected by current assays.

Françoise Benoit-Vical, PhD, of Université de Toulouse in France, and his colleagues described this work in Emerging Infectious Diseases.

The researchers set out to study resistance mechanisms in Plasmodium falciparum parasites. So they exposed the parasites to artemisinin in vitro for 5 years.

Parasites that survived in the presence of artemisinin developed resistance to most other artemisinin-based or non-artemisinin-based antimalarial therapies, including partner molecules present in combination therapies used in endemic areas.

These parasites did not exhibit any known mutation in resistance genes. However, the researchers found the parasites could circumvent the toxic effect of the drugs by quiescence.

The parasites were able to suspend their development during exposure to antimalarial agents. As soon as they were no longer subjected to antimalarial therapy, they “woke up” and began to proliferate again.

The researchers also found that multidrug resistance based on this quiescence phenomenon cannot be detected by tests currently used to analyze parasitic resistance.

“In vitro tests carried out using the patient’s blood predict high sensitivity and, therefore, the treatment’s effectiveness, while parasites are resistant because they are quiescent,” Dr Benoit-Vical said.

“As such, it is essential to conduct research with relevant and appropriate tests in the field if the multi[drug]-resistant phenomenon that we identified in vitro is also present, in order to design therapeutic strategies accordingly.”

Malaria-infected cell bursting

Image by Peter H. Seeberger

Researchers say they have identified a mechanism of multidrug resistance in malaria that represents a major threat to antimalarial drug policy.

The team exposed a strain of malaria parasites to artemisinin (the base compound for standard therapy) long-term and found the parasites developed widespread resistance to most other antimalarial drugs.

The group also discovered that this type of resistance cannot be detected by current assays.

Françoise Benoit-Vical, PhD, of Université de Toulouse in France, and his colleagues described this work in Emerging Infectious Diseases.

The researchers set out to study resistance mechanisms in Plasmodium falciparum parasites. So they exposed the parasites to artemisinin in vitro for 5 years.

Parasites that survived in the presence of artemisinin developed resistance to most other artemisinin-based or non-artemisinin-based antimalarial therapies, including partner molecules present in combination therapies used in endemic areas.

These parasites did not exhibit any known mutation in resistance genes. However, the researchers found the parasites could circumvent the toxic effect of the drugs by quiescence.

The parasites were able to suspend their development during exposure to antimalarial agents. As soon as they were no longer subjected to antimalarial therapy, they “woke up” and began to proliferate again.

The researchers also found that multidrug resistance based on this quiescence phenomenon cannot be detected by tests currently used to analyze parasitic resistance.

“In vitro tests carried out using the patient’s blood predict high sensitivity and, therefore, the treatment’s effectiveness, while parasites are resistant because they are quiescent,” Dr Benoit-Vical said.

“As such, it is essential to conduct research with relevant and appropriate tests in the field if the multi[drug]-resistant phenomenon that we identified in vitro is also present, in order to design therapeutic strategies accordingly.”

Malaria-infected cell bursting

Image by Peter H. Seeberger

Researchers say they have identified a mechanism of multidrug resistance in malaria that represents a major threat to antimalarial drug policy.

The team exposed a strain of malaria parasites to artemisinin (the base compound for standard therapy) long-term and found the parasites developed widespread resistance to most other antimalarial drugs.

The group also discovered that this type of resistance cannot be detected by current assays.

Françoise Benoit-Vical, PhD, of Université de Toulouse in France, and his colleagues described this work in Emerging Infectious Diseases.

The researchers set out to study resistance mechanisms in Plasmodium falciparum parasites. So they exposed the parasites to artemisinin in vitro for 5 years.

Parasites that survived in the presence of artemisinin developed resistance to most other artemisinin-based or non-artemisinin-based antimalarial therapies, including partner molecules present in combination therapies used in endemic areas.

These parasites did not exhibit any known mutation in resistance genes. However, the researchers found the parasites could circumvent the toxic effect of the drugs by quiescence.

The parasites were able to suspend their development during exposure to antimalarial agents. As soon as they were no longer subjected to antimalarial therapy, they “woke up” and began to proliferate again.

The researchers also found that multidrug resistance based on this quiescence phenomenon cannot be detected by tests currently used to analyze parasitic resistance.

“In vitro tests carried out using the patient’s blood predict high sensitivity and, therefore, the treatment’s effectiveness, while parasites are resistant because they are quiescent,” Dr Benoit-Vical said.

“As such, it is essential to conduct research with relevant and appropriate tests in the field if the multi[drug]-resistant phenomenon that we identified in vitro is also present, in order to design therapeutic strategies accordingly.”

Researcher in the lab

Photo by Daniel Sone

A new report suggests a need to change regulations for federally funded research in the US.

According to the report, the current regulatory burden is diminishing the effectiveness of the US scientific enterprise and lowering the return on

the federal investment in research by directing investigators’ time away from research and toward administrative matters.

The report, Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century: Part 1 (2015), was

compiled by the National Academies of Sciences, Engineering, and Medicine.

“Federal regulations and reporting requirements, which began as a way to exercise responsible oversight, have increased dramatically in recent

decades and are now unduly encumbering the very research enterprise they were intended to facilitate,” said Larry Faulkner, chair of the committee that conducted the study and wrote the report, and president emeritus of the University of Texas, Austin.

“A significant amount of investigators’ time is now spent complying with regulations, taking valuable time from research, teaching, and scholarship.”

The report lists specific actions the government and research institutions should take to reduce the regulatory burden.

New framework needed

The report says a new framework is needed to approach regulation in a holistic, rather than piecemeal, way. Regulatory requirements should be harmonized across funding agencies, and we need a more effective and efficient partnership between funding agencies and research institutions.

Congress should create a Research Policy Board to serve as a public-private forum for discussions related to regulation of federally funded research programs. The board should be a government-enabled, private-sector entity that will foster more effective conception, development, and synchronization of research policies.

The board should be formally connected to government through a new associate director position at the White House Office of Science and Technology Policy (OSTP) and through the Office of Information and Regulatory Affairs at the White House Office of Management and Budget (OMB).

Strengthening the research partnership also requires that universities demand the highest standards in institutional and individual behavior, foster a culture of integrity, and mete out appropriate sanctions when behavior deviates from ethical and professional norms, the report says.

The Research Policy Board should collaborate with research institutions to develop a policy that holds universities accountable, sanctioning institutions that fail to enforce standards.

The report also recommends a number of specific actions—a sample of which are listed below—that are intended to improve the efficiency of federal regulation and reduce duplication.

Congress should:

• Work with OMB to conduct a review of agency research grant proposal documents for the purpose of developing a uniform format to be used by all funding agencies
• Work with OSTP and research institutions to develop a single financial conflict-of-interest policy to be used by all research funding agencies
• Task a single agency with overseeing and unifying efforts to develop a central database of investigators and their professional output
• Direct agencies to align and harmonize their regulations and definitions concerning the protection of human subjects
• Instruct OSTP to convene representatives from federal agencies that fund animal research and from the research community to assess and report back to Congress on the feasibility and usefulness of a unified federal approach to policies and regulations pertaining to the care and use of research animals.

The White House OMB should:

• Require that research funding agencies use a uniform format for research progress reporting
• Amend the new Uniform Guidance to improve the efficiency and consistency of procurement standards, financial reporting, and cost accounting.

Federal agencies should:

• Limit research proposals to the minimum information necessary to permit peer evaluation of the merit of the scientific questions being asked, the feasibility of answering those questions, and the ability of the investigator to carry out that research. Any supplementary information—internal review board approval, conflict-of-interest disclosures, detailed budgets, etc.—should be provided “just in time,” after the research proposal is deemed likely to be funded
• Reduce and streamline reporting, assurances, and verifications. Agencies should also develop a central repository to house assurances.

Universities should:

• Conduct a review of institutional policies developed to comply with federal regulations of research to determine whether the institution itself has created excessive or unnecessary self-imposed burden
• Revise self-imposed burdensome institutional policies that go beyond those necessary and sufficient to comply with federal, state, and local requirements.

The release of the report completes the first phase of the committee’s study, which was expedited at the request of Congress.

The committee will now continue its assessment and issue a spring 2016 addendum report addressing issues it has been unable to address in the first phase.

Researcher in the lab

Photo by Daniel Sone

A new report suggests a need to change regulations for federally funded research in the US.

According to the report, the current regulatory burden is diminishing the effectiveness of the US scientific enterprise and lowering the return on

the federal investment in research by directing investigators’ time away from research and toward administrative matters.

The report, Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century: Part 1 (2015), was

compiled by the National Academies of Sciences, Engineering, and Medicine.

“Federal regulations and reporting requirements, which began as a way to exercise responsible oversight, have increased dramatically in recent

decades and are now unduly encumbering the very research enterprise they were intended to facilitate,” said Larry Faulkner, chair of the committee that conducted the study and wrote the report, and president emeritus of the University of Texas, Austin.

“A significant amount of investigators’ time is now spent complying with regulations, taking valuable time from research, teaching, and scholarship.”

The report lists specific actions the government and research institutions should take to reduce the regulatory burden.

New framework needed

The report says a new framework is needed to approach regulation in a holistic, rather than piecemeal, way. Regulatory requirements should be harmonized across funding agencies, and we need a more effective and efficient partnership between funding agencies and research institutions.

Congress should create a Research Policy Board to serve as a public-private forum for discussions related to regulation of federally funded research programs. The board should be a government-enabled, private-sector entity that will foster more effective conception, development, and synchronization of research policies.

The board should be formally connected to government through a new associate director position at the White House Office of Science and Technology Policy (OSTP) and through the Office of Information and Regulatory Affairs at the White House Office of Management and Budget (OMB).

Strengthening the research partnership also requires that universities demand the highest standards in institutional and individual behavior, foster a culture of integrity, and mete out appropriate sanctions when behavior deviates from ethical and professional norms, the report says.

The Research Policy Board should collaborate with research institutions to develop a policy that holds universities accountable, sanctioning institutions that fail to enforce standards.

The report also recommends a number of specific actions—a sample of which are listed below—that are intended to improve the efficiency of federal regulation and reduce duplication.

Congress should:

• Work with OMB to conduct a review of agency research grant proposal documents for the purpose of developing a uniform format to be used by all funding agencies
• Work with OSTP and research institutions to develop a single financial conflict-of-interest policy to be used by all research funding agencies
• Task a single agency with overseeing and unifying efforts to develop a central database of investigators and their professional output
• Direct agencies to align and harmonize their regulations and definitions concerning the protection of human subjects
• Instruct OSTP to convene representatives from federal agencies that fund animal research and from the research community to assess and report back to Congress on the feasibility and usefulness of a unified federal approach to policies and regulations pertaining to the care and use of research animals.

The White House OMB should:

• Require that research funding agencies use a uniform format for research progress reporting
• Amend the new Uniform Guidance to improve the efficiency and consistency of procurement standards, financial reporting, and cost accounting.

Federal agencies should:

• Limit research proposals to the minimum information necessary to permit peer evaluation of the merit of the scientific questions being asked, the feasibility of answering those questions, and the ability of the investigator to carry out that research. Any supplementary information—internal review board approval, conflict-of-interest disclosures, detailed budgets, etc.—should be provided “just in time,” after the research proposal is deemed likely to be funded
• Reduce and streamline reporting, assurances, and verifications. Agencies should also develop a central repository to house assurances.

Universities should:

• Conduct a review of institutional policies developed to comply with federal regulations of research to determine whether the institution itself has created excessive or unnecessary self-imposed burden
• Revise self-imposed burdensome institutional policies that go beyond those necessary and sufficient to comply with federal, state, and local requirements.

The release of the report completes the first phase of the committee’s study, which was expedited at the request of Congress.

The committee will now continue its assessment and issue a spring 2016 addendum report addressing issues it has been unable to address in the first phase.

Researcher in the lab

Photo by Daniel Sone

A new report suggests a need to change regulations for federally funded research in the US.

According to the report, the current regulatory burden is diminishing the effectiveness of the US scientific enterprise and lowering the return on

the federal investment in research by directing investigators’ time away from research and toward administrative matters.

The report, Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century: Part 1 (2015), was

compiled by the National Academies of Sciences, Engineering, and Medicine.

“Federal regulations and reporting requirements, which began as a way to exercise responsible oversight, have increased dramatically in recent

decades and are now unduly encumbering the very research enterprise they were intended to facilitate,” said Larry Faulkner, chair of the committee that conducted the study and wrote the report, and president emeritus of the University of Texas, Austin.

“A significant amount of investigators’ time is now spent complying with regulations, taking valuable time from research, teaching, and scholarship.”

The report lists specific actions the government and research institutions should take to reduce the regulatory burden.

New framework needed

The report says a new framework is needed to approach regulation in a holistic, rather than piecemeal, way. Regulatory requirements should be harmonized across funding agencies, and we need a more effective and efficient partnership between funding agencies and research institutions.

Congress should create a Research Policy Board to serve as a public-private forum for discussions related to regulation of federally funded research programs. The board should be a government-enabled, private-sector entity that will foster more effective conception, development, and synchronization of research policies.

The board should be formally connected to government through a new associate director position at the White House Office of Science and Technology Policy (OSTP) and through the Office of Information and Regulatory Affairs at the White House Office of Management and Budget (OMB).

Strengthening the research partnership also requires that universities demand the highest standards in institutional and individual behavior, foster a culture of integrity, and mete out appropriate sanctions when behavior deviates from ethical and professional norms, the report says.

The Research Policy Board should collaborate with research institutions to develop a policy that holds universities accountable, sanctioning institutions that fail to enforce standards.

The report also recommends a number of specific actions—a sample of which are listed below—that are intended to improve the efficiency of federal regulation and reduce duplication.

Congress should:

• Work with OMB to conduct a review of agency research grant proposal documents for the purpose of developing a uniform format to be used by all funding agencies
• Work with OSTP and research institutions to develop a single financial conflict-of-interest policy to be used by all research funding agencies
• Task a single agency with overseeing and unifying efforts to develop a central database of investigators and their professional output
• Direct agencies to align and harmonize their regulations and definitions concerning the protection of human subjects
• Instruct OSTP to convene representatives from federal agencies that fund animal research and from the research community to assess and report back to Congress on the feasibility and usefulness of a unified federal approach to policies and regulations pertaining to the care and use of research animals.

The White House OMB should:

• Require that research funding agencies use a uniform format for research progress reporting
• Amend the new Uniform Guidance to improve the efficiency and consistency of procurement standards, financial reporting, and cost accounting.

Federal agencies should:

• Limit research proposals to the minimum information necessary to permit peer evaluation of the merit of the scientific questions being asked, the feasibility of answering those questions, and the ability of the investigator to carry out that research. Any supplementary information—internal review board approval, conflict-of-interest disclosures, detailed budgets, etc.—should be provided “just in time,” after the research proposal is deemed likely to be funded
• Reduce and streamline reporting, assurances, and verifications. Agencies should also develop a central repository to house assurances.

Universities should:

• Conduct a review of institutional policies developed to comply with federal regulations of research to determine whether the institution itself has created excessive or unnecessary self-imposed burden
• Revise self-imposed burdensome institutional policies that go beyond those necessary and sufficient to comply with federal, state, and local requirements.

The release of the report completes the first phase of the committee’s study, which was expedited at the request of Congress.

The committee will now continue its assessment and issue a spring 2016 addendum report addressing issues it has been unable to address in the first phase.

Brentuximab vedotin

Photo from Business Wire

First-line treatment with brentuximab vedotin (BV) can produce a high response rate in older Hodgkin lymphoma (HL) patients who are unfit for chemotherapy, according to research published in Blood.

In this small study, single-agent BV produced an overall response rate of 92% and a complete response rate of 73%.

However, the drug also produced a high rate of peripheral sensory neuropathy (78%), which was the most common adverse event.

This phase 2 trial is the first to assess BV as front-line treatment. The study was funded by Seattle Genetics, Inc., which is developing BV in collaboration with Takeda Pharmaceutical Company.

Andres Forero-Torres, MD, of the University of Alabama at Birmingham, and his colleagues conducted the research, enrolling 27 HL patients (ages 64 to 92) in the trial.

The patients were either ineligible for conventional chemotherapy or declined treatment after receiving information about its risks.

They received 1.8 mg/kg of intravenous BV every 3 weeks for up to 16 doses. Those who benefitted from the drug could continue beyond this time period until disease progression, unacceptable toxicity, or study closure.

Patients received a median of 8 cycles, with 4 patients completing 16 cycles and 1 patient completing 23 cycles.

Peripheral neuropathy was the primary adverse event leading to dose modifications. Fourteen patients (52%) had dose delays, typically lasting a week (range, 1 to 3). But 11 patients (41%) had permanent dose reductions to 1.2 mg/kg.

Safety

All 27 patients were evaluable for safety, and all experienced at least 1 adverse event. The most commonly reported events were peripheral sensory neuropathy (n=21, 78%), fatigue (n=12, 44%), and nausea (n=12, 44%).

Treatment-emergent grade 3 adverse events included peripheral sensory neuropathy (n=7, 26%), rash (n=2, 7%), urinary tract infection (n=1, 4%), and maculopapular rash (n=1, 4%)

There were 2 grade 4 events—hyperuricemia and drug hypersensitivity to anesthesia—considered unrelated to BV.

Efficacy

Twenty-six patients were evaluable for efficacy. One patient was found to have nodular lymphocyte predominant HL and was therefore excluded.

The overall response rate was 92%. Nineteen patients had a complete response, 5 had a partial response, and 2 had stable disease.

The median duration of response was about 9.1 months (range, 2.8 to 20.9+ months).

The median progression-free survival was 10.5 months (range, 2.6+ to 22.3+ months), and the median overall survival had not been reached at the time of analysis (range, 4.6+ to 24.9+ months).

“While we observed promising responses,” Dr Forero-Torres said, “the next step is to evaluate this drug in combination with additional chemotherapy or immunotherapies that might allow us to prolong the response without relapse.”

Brentuximab vedotin

Photo from Business Wire

First-line treatment with brentuximab vedotin (BV) can produce a high response rate in older Hodgkin lymphoma (HL) patients who are unfit for chemotherapy, according to research published in Blood.

In this small study, single-agent BV produced an overall response rate of 92% and a complete response rate of 73%.

However, the drug also produced a high rate of peripheral sensory neuropathy (78%), which was the most common adverse event.

This phase 2 trial is the first to assess BV as front-line treatment. The study was funded by Seattle Genetics, Inc., which is developing BV in collaboration with Takeda Pharmaceutical Company.

Andres Forero-Torres, MD, of the University of Alabama at Birmingham, and his colleagues conducted the research, enrolling 27 HL patients (ages 64 to 92) in the trial.

The patients were either ineligible for conventional chemotherapy or declined treatment after receiving information about its risks.

They received 1.8 mg/kg of intravenous BV every 3 weeks for up to 16 doses. Those who benefitted from the drug could continue beyond this time period until disease progression, unacceptable toxicity, or study closure.

Patients received a median of 8 cycles, with 4 patients completing 16 cycles and 1 patient completing 23 cycles.

Peripheral neuropathy was the primary adverse event leading to dose modifications. Fourteen patients (52%) had dose delays, typically lasting a week (range, 1 to 3). But 11 patients (41%) had permanent dose reductions to 1.2 mg/kg.

Safety

All 27 patients were evaluable for safety, and all experienced at least 1 adverse event. The most commonly reported events were peripheral sensory neuropathy (n=21, 78%), fatigue (n=12, 44%), and nausea (n=12, 44%).

Treatment-emergent grade 3 adverse events included peripheral sensory neuropathy (n=7, 26%), rash (n=2, 7%), urinary tract infection (n=1, 4%), and maculopapular rash (n=1, 4%)

There were 2 grade 4 events—hyperuricemia and drug hypersensitivity to anesthesia—considered unrelated to BV.

Efficacy

Twenty-six patients were evaluable for efficacy. One patient was found to have nodular lymphocyte predominant HL and was therefore excluded.

The overall response rate was 92%. Nineteen patients had a complete response, 5 had a partial response, and 2 had stable disease.

The median duration of response was about 9.1 months (range, 2.8 to 20.9+ months).

The median progression-free survival was 10.5 months (range, 2.6+ to 22.3+ months), and the median overall survival had not been reached at the time of analysis (range, 4.6+ to 24.9+ months).

“While we observed promising responses,” Dr Forero-Torres said, “the next step is to evaluate this drug in combination with additional chemotherapy or immunotherapies that might allow us to prolong the response without relapse.”

Brentuximab vedotin

Photo from Business Wire

First-line treatment with brentuximab vedotin (BV) can produce a high response rate in older Hodgkin lymphoma (HL) patients who are unfit for chemotherapy, according to research published in Blood.

In this small study, single-agent BV produced an overall response rate of 92% and a complete response rate of 73%.

However, the drug also produced a high rate of peripheral sensory neuropathy (78%), which was the most common adverse event.

This phase 2 trial is the first to assess BV as front-line treatment. The study was funded by Seattle Genetics, Inc., which is developing BV in collaboration with Takeda Pharmaceutical Company.

Andres Forero-Torres, MD, of the University of Alabama at Birmingham, and his colleagues conducted the research, enrolling 27 HL patients (ages 64 to 92) in the trial.

The patients were either ineligible for conventional chemotherapy or declined treatment after receiving information about its risks.

They received 1.8 mg/kg of intravenous BV every 3 weeks for up to 16 doses. Those who benefitted from the drug could continue beyond this time period until disease progression, unacceptable toxicity, or study closure.

Patients received a median of 8 cycles, with 4 patients completing 16 cycles and 1 patient completing 23 cycles.

Peripheral neuropathy was the primary adverse event leading to dose modifications. Fourteen patients (52%) had dose delays, typically lasting a week (range, 1 to 3). But 11 patients (41%) had permanent dose reductions to 1.2 mg/kg.

Safety

All 27 patients were evaluable for safety, and all experienced at least 1 adverse event. The most commonly reported events were peripheral sensory neuropathy (n=21, 78%), fatigue (n=12, 44%), and nausea (n=12, 44%).

Treatment-emergent grade 3 adverse events included peripheral sensory neuropathy (n=7, 26%), rash (n=2, 7%), urinary tract infection (n=1, 4%), and maculopapular rash (n=1, 4%)

There were 2 grade 4 events—hyperuricemia and drug hypersensitivity to anesthesia—considered unrelated to BV.

Efficacy

Twenty-six patients were evaluable for efficacy. One patient was found to have nodular lymphocyte predominant HL and was therefore excluded.

The overall response rate was 92%. Nineteen patients had a complete response, 5 had a partial response, and 2 had stable disease.

The median duration of response was about 9.1 months (range, 2.8 to 20.9+ months).

The median progression-free survival was 10.5 months (range, 2.6+ to 22.3+ months), and the median overall survival had not been reached at the time of analysis (range, 4.6+ to 24.9+ months).

“While we observed promising responses,” Dr Forero-Torres said, “the next step is to evaluate this drug in combination with additional chemotherapy or immunotherapies that might allow us to prolong the response without relapse.”

Doctor and patient in hospital

Photo courtesy of the CDC

SAN DIEGO—A retrospective study has provided insight into hospital readmissions related to opportunistic infection following hematopoietic stem cell transplant (HSCT).

Of the roughly 4200 HSCT recipients studied, 26% were readmitted to the hospital due to opportunistic infection.

About 1 in 3 infection-related readmissions were due to double-stranded DNA (dsDNA) viral infections, and cytomegalovirus (CMV) infections were the most common.

Nearly half of the dsDNA viral infections occurred within the first month of HSCT discharge.

These findings were presented at ICAAC/ICC 2015 (poster T-1360). The study was sponsored by Chimerix, Inc.

Investigators searched the Premier hospital database for patients who underwent HSCT between January 2009 and September 2013. The team identified 4393 patients with a mean age of 50.4 years. Most were adults (91.2%), most were male (57.9%), and most received an autologous HSCT (63.2%).

About 42% (n=1841) of patients had a diagnostic code for opportunistic infection in their HSCT discharge records. Overall, 7.3% (n=319) of patients had dsDNA virus infections, including 13.4% (n=216) of patients who received an allogeneic HSCT.

One hundred and fifty-seven patients died during HSCT hospitalization, leaving 4236 patients evaluable for readmission analysis.

In all, 37.7% (n=1595) of the surviving patients were readmitted to the hospital for any reason during the 12 months after HSCT discharge. And 65.6% of the readmissions occurred within the first 3 months of HSCT discharge.

Readmissions were most frequently related to opportunistic infections (25.8%, n=1091), followed by graft-versus-host disease (13.7%, n=579), renal impairment (11.1%, n=470), and neutropenia (10.0%, n=422).

The investigators noted that patients may have had multiple readmissions or readmission with multiple diagnoses.

Of the hospital readmissions related to opportunistic infections, 32.0% (n=349) were related to dsDNA virus infections. This included CMV (65.9%, n=230), BK virus (13.8%, n=48), adenovirus (5.2%, n=18), and other dsDNA virus infections (32.7%, n=114).

Patients may have experienced more than one viral infection, so the number of hospital readmissions related to each dsDNA virus was not mutually exclusive.

Readmission within the first month of HSCT discharge occurred in 41.8% of patients with any dsDNA virus infection, 49.6% with CMV infection, and 56.3% with BK virus infection. More than half (55.6%) of readmissions related to adenovirus infection occurred within the first 3 months of HSCT discharge.

Taking these results together, the investigators concluded that hospital readmissions related to opportunistic infections were relatively common among HSCT recipients. So strategies that minimize the risks of these infections might have significant clinical and economic advantages.

Doctor and patient in hospital

Photo courtesy of the CDC

SAN DIEGO—A retrospective study has provided insight into hospital readmissions related to opportunistic infection following hematopoietic stem cell transplant (HSCT).

Of the roughly 4200 HSCT recipients studied, 26% were readmitted to the hospital due to opportunistic infection.

About 1 in 3 infection-related readmissions were due to double-stranded DNA (dsDNA) viral infections, and cytomegalovirus (CMV) infections were the most common.

Nearly half of the dsDNA viral infections occurred within the first month of HSCT discharge.

These findings were presented at ICAAC/ICC 2015 (poster T-1360). The study was sponsored by Chimerix, Inc.

Investigators searched the Premier hospital database for patients who underwent HSCT between January 2009 and September 2013. The team identified 4393 patients with a mean age of 50.4 years. Most were adults (91.2%), most were male (57.9%), and most received an autologous HSCT (63.2%).

About 42% (n=1841) of patients had a diagnostic code for opportunistic infection in their HSCT discharge records. Overall, 7.3% (n=319) of patients had dsDNA virus infections, including 13.4% (n=216) of patients who received an allogeneic HSCT.

One hundred and fifty-seven patients died during HSCT hospitalization, leaving 4236 patients evaluable for readmission analysis.

In all, 37.7% (n=1595) of the surviving patients were readmitted to the hospital for any reason during the 12 months after HSCT discharge. And 65.6% of the readmissions occurred within the first 3 months of HSCT discharge.

Readmissions were most frequently related to opportunistic infections (25.8%, n=1091), followed by graft-versus-host disease (13.7%, n=579), renal impairment (11.1%, n=470), and neutropenia (10.0%, n=422).

The investigators noted that patients may have had multiple readmissions or readmission with multiple diagnoses.

Of the hospital readmissions related to opportunistic infections, 32.0% (n=349) were related to dsDNA virus infections. This included CMV (65.9%, n=230), BK virus (13.8%, n=48), adenovirus (5.2%, n=18), and other dsDNA virus infections (32.7%, n=114).

Patients may have experienced more than one viral infection, so the number of hospital readmissions related to each dsDNA virus was not mutually exclusive.

Readmission within the first month of HSCT discharge occurred in 41.8% of patients with any dsDNA virus infection, 49.6% with CMV infection, and 56.3% with BK virus infection. More than half (55.6%) of readmissions related to adenovirus infection occurred within the first 3 months of HSCT discharge.

Taking these results together, the investigators concluded that hospital readmissions related to opportunistic infections were relatively common among HSCT recipients. So strategies that minimize the risks of these infections might have significant clinical and economic advantages.

Doctor and patient in hospital

Photo courtesy of the CDC

SAN DIEGO—A retrospective study has provided insight into hospital readmissions related to opportunistic infection following hematopoietic stem cell transplant (HSCT).

Of the roughly 4200 HSCT recipients studied, 26% were readmitted to the hospital due to opportunistic infection.

About 1 in 3 infection-related readmissions were due to double-stranded DNA (dsDNA) viral infections, and cytomegalovirus (CMV) infections were the most common.

Nearly half of the dsDNA viral infections occurred within the first month of HSCT discharge.

These findings were presented at ICAAC/ICC 2015 (poster T-1360). The study was sponsored by Chimerix, Inc.

Investigators searched the Premier hospital database for patients who underwent HSCT between January 2009 and September 2013. The team identified 4393 patients with a mean age of 50.4 years. Most were adults (91.2%), most were male (57.9%), and most received an autologous HSCT (63.2%).

About 42% (n=1841) of patients had a diagnostic code for opportunistic infection in their HSCT discharge records. Overall, 7.3% (n=319) of patients had dsDNA virus infections, including 13.4% (n=216) of patients who received an allogeneic HSCT.

One hundred and fifty-seven patients died during HSCT hospitalization, leaving 4236 patients evaluable for readmission analysis.

In all, 37.7% (n=1595) of the surviving patients were readmitted to the hospital for any reason during the 12 months after HSCT discharge. And 65.6% of the readmissions occurred within the first 3 months of HSCT discharge.

Readmissions were most frequently related to opportunistic infections (25.8%, n=1091), followed by graft-versus-host disease (13.7%, n=579), renal impairment (11.1%, n=470), and neutropenia (10.0%, n=422).

The investigators noted that patients may have had multiple readmissions or readmission with multiple diagnoses.

Of the hospital readmissions related to opportunistic infections, 32.0% (n=349) were related to dsDNA virus infections. This included CMV (65.9%, n=230), BK virus (13.8%, n=48), adenovirus (5.2%, n=18), and other dsDNA virus infections (32.7%, n=114).

Patients may have experienced more than one viral infection, so the number of hospital readmissions related to each dsDNA virus was not mutually exclusive.

Readmission within the first month of HSCT discharge occurred in 41.8% of patients with any dsDNA virus infection, 49.6% with CMV infection, and 56.3% with BK virus infection. More than half (55.6%) of readmissions related to adenovirus infection occurred within the first 3 months of HSCT discharge.

Taking these results together, the investigators concluded that hospital readmissions related to opportunistic infections were relatively common among HSCT recipients. So strategies that minimize the risks of these infections might have significant clinical and economic advantages.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted priority review for an application for ofatumumab (Arzerra) as maintenance therapy in

patients with relapsed chronic lymphocytic leukemia (CLL).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Ofatumumab is a human monoclonal antibody (mAb) designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

The mAb is already FDA-approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is also approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA said it aims to complete its review of the application for ofatumumab as maintenance therapy in relapsed CLL by January 21, 2016.

PROLONG trial

The application for ofatumumab as maintenance is based on interim results from the phase 3 PROLONG (OMB112517) trial, which were presented at ASH 2014.

In this trial, researchers compared ofatumumab maintenance to no further treatment in patients with a complete or partial response after second-

or third-line treatment for CLL.

Interim results suggested that ofatumumab significantly improves progression-free survival but not overall survival.

The median progression-free survival was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive

maintenance (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

Ofatumumab development

Ofatumumab is approved in more than 50 countries worldwide as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

In the European Union, ofatumumab is approved for use in combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and who are not eligible for fludarabine-based therapy.

Ofatumumab is not approved anywhere in the world as maintenance therapy for relapsed CLL. The drug is being developed by Genmab and Novartis.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted priority review for an application for ofatumumab (Arzerra) as maintenance therapy in

patients with relapsed chronic lymphocytic leukemia (CLL).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Ofatumumab is a human monoclonal antibody (mAb) designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

The mAb is already FDA-approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is also approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA said it aims to complete its review of the application for ofatumumab as maintenance therapy in relapsed CLL by January 21, 2016.

PROLONG trial

The application for ofatumumab as maintenance is based on interim results from the phase 3 PROLONG (OMB112517) trial, which were presented at ASH 2014.

In this trial, researchers compared ofatumumab maintenance to no further treatment in patients with a complete or partial response after second-

or third-line treatment for CLL.

Interim results suggested that ofatumumab significantly improves progression-free survival but not overall survival.

The median progression-free survival was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive

maintenance (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

Ofatumumab development

Ofatumumab is approved in more than 50 countries worldwide as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

In the European Union, ofatumumab is approved for use in combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and who are not eligible for fludarabine-based therapy.

Ofatumumab is not approved anywhere in the world as maintenance therapy for relapsed CLL. The drug is being developed by Genmab and Novartis.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted priority review for an application for ofatumumab (Arzerra) as maintenance therapy in

patients with relapsed chronic lymphocytic leukemia (CLL).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Ofatumumab is a human monoclonal antibody (mAb) designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

The mAb is already FDA-approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is also approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA said it aims to complete its review of the application for ofatumumab as maintenance therapy in relapsed CLL by January 21, 2016.

PROLONG trial

The application for ofatumumab as maintenance is based on interim results from the phase 3 PROLONG (OMB112517) trial, which were presented at ASH 2014.

In this trial, researchers compared ofatumumab maintenance to no further treatment in patients with a complete or partial response after second-

or third-line treatment for CLL.

Interim results suggested that ofatumumab significantly improves progression-free survival but not overall survival.

The median progression-free survival was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive

maintenance (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

Ofatumumab development

Ofatumumab is approved in more than 50 countries worldwide as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

In the European Union, ofatumumab is approved for use in combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and who are not eligible for fludarabine-based therapy.

Ofatumumab is not approved anywhere in the world as maintenance therapy for relapsed CLL. The drug is being developed by Genmab and Novartis.

Diffuse large B-cell lymphoma

HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.

Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.

New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.

Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.

The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.

Results in AML

Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.

CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.

The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.

They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.

B-cell lymphomas

In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).

CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).

The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).

The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.

CYC065 in combination

CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.

CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.

Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.

And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.

Diffuse large B-cell lymphoma

HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.

Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.

New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.

Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.

The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.

Results in AML

Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.

CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.

The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.

They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.

B-cell lymphomas

In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).

CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).

The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).

The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.

CYC065 in combination

CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.

CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.

Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.

And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.

Diffuse large B-cell lymphoma

HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.

Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.

New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.

Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.

The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.

Results in AML

Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.

CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.

The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.

They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.

B-cell lymphomas

In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).

CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).

The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).

The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.

CYC065 in combination

CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.

CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.

Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.

And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.