Anemia

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

Doctor with clipboard

A questionnaire may help aid the transition from pediatric to adult care for patients with sickle cell disease (SCD), according to a paper published in the Journal of Pediatric Hematology/Oncology.

Researchers showed that the questionnaire could pinpoint areas in which young SCD patients may need help to transition to an adult clinic.

The questionnaire measured 5 knowledge skill sets—medical, educational/vocational, health benefits, social, and independent living—as well as 3 psychological assessments—feelings, stress, and self-efficacy.

To test how effective the questionnaire can be, Amy Sobota, MD, of Boston Medical Center, and her colleagues looked at the answers provided by 33 patients between the ages of 18 and 22.

Most respondents had good medical knowledge of SCD. Ninety-seven percent said they could explain SCD to another person and understood “how they got” the disease.

Ninety-four percent of patients also understood that SCD might be passed on to their children, and 71% of women said they knew how SCD could affect their pregnancy. However, only 30% of patients reported knowing what their baseline hemoglobin level is.

Likewise, the questionnaire suggested some knowledge gaps with regard to health benefits. Sixty-four percent of patients said they understood the various types of health insurance available to them, and 61% knew how their age could affect their health benefits.

Patients’ educational/vocational knowledge and capabilities were promising overall. Ninety-one percent of patients said they had a specific plan for the future, and 94% said they knew the education or employment required for their job choice. Seventy-six percent said they could identify the type of work that could cause problems related to SCD.

As for independent living, 91% of patients said they could fill their prescriptions on their own, 85% could make doctor’s appointments on their own, and 79% reported going to doctor’s appointments on their own.

With regard to social support, 97% of patients said they had a good social support system. But fewer (70%) had friends they could talk to about SCD, and only 48% knew about community-based SCD programs.

Most patients said they were worried that SCD would hinder them in some ways. Seventy-six percent worried about SCD getting in the way of school or work, and 51% worried it might prevent them from doing things they enjoy.

However, most patients felt sure they could function well. Eighty-eight percent said they could keep doing most of the things they do day-to-day, and 54% said they had ways of managing their pain without medication.

A minority of patients were worried or anxious about transitioning to adult care. Twenty-five percent were “quite a bit” or “extremely” worried, and 9% were similarly anxious about the transition. Sixteen percent said they felt “not at all” or “a little bit” all right to transition to an adult health care setting.

“Our study indicates that this assessment tool—the only one of its kind—provides important information to physicians of patients with sickle cell disease who are transitioning from pediatric to adult care,” Dr Sobota said. “Caregivers can use this information from patients in order to effectively tailor and guide their treatment and education through this transition.”

Doctor with clipboard

A questionnaire may help aid the transition from pediatric to adult care for patients with sickle cell disease (SCD), according to a paper published in the Journal of Pediatric Hematology/Oncology.

Researchers showed that the questionnaire could pinpoint areas in which young SCD patients may need help to transition to an adult clinic.

The questionnaire measured 5 knowledge skill sets—medical, educational/vocational, health benefits, social, and independent living—as well as 3 psychological assessments—feelings, stress, and self-efficacy.

To test how effective the questionnaire can be, Amy Sobota, MD, of Boston Medical Center, and her colleagues looked at the answers provided by 33 patients between the ages of 18 and 22.

Most respondents had good medical knowledge of SCD. Ninety-seven percent said they could explain SCD to another person and understood “how they got” the disease.

Ninety-four percent of patients also understood that SCD might be passed on to their children, and 71% of women said they knew how SCD could affect their pregnancy. However, only 30% of patients reported knowing what their baseline hemoglobin level is.

Likewise, the questionnaire suggested some knowledge gaps with regard to health benefits. Sixty-four percent of patients said they understood the various types of health insurance available to them, and 61% knew how their age could affect their health benefits.

Patients’ educational/vocational knowledge and capabilities were promising overall. Ninety-one percent of patients said they had a specific plan for the future, and 94% said they knew the education or employment required for their job choice. Seventy-six percent said they could identify the type of work that could cause problems related to SCD.

As for independent living, 91% of patients said they could fill their prescriptions on their own, 85% could make doctor’s appointments on their own, and 79% reported going to doctor’s appointments on their own.

With regard to social support, 97% of patients said they had a good social support system. But fewer (70%) had friends they could talk to about SCD, and only 48% knew about community-based SCD programs.

Most patients said they were worried that SCD would hinder them in some ways. Seventy-six percent worried about SCD getting in the way of school or work, and 51% worried it might prevent them from doing things they enjoy.

However, most patients felt sure they could function well. Eighty-eight percent said they could keep doing most of the things they do day-to-day, and 54% said they had ways of managing their pain without medication.

A minority of patients were worried or anxious about transitioning to adult care. Twenty-five percent were “quite a bit” or “extremely” worried, and 9% were similarly anxious about the transition. Sixteen percent said they felt “not at all” or “a little bit” all right to transition to an adult health care setting.

“Our study indicates that this assessment tool—the only one of its kind—provides important information to physicians of patients with sickle cell disease who are transitioning from pediatric to adult care,” Dr Sobota said. “Caregivers can use this information from patients in order to effectively tailor and guide their treatment and education through this transition.”

Doctor with clipboard

A questionnaire may help aid the transition from pediatric to adult care for patients with sickle cell disease (SCD), according to a paper published in the Journal of Pediatric Hematology/Oncology.

Researchers showed that the questionnaire could pinpoint areas in which young SCD patients may need help to transition to an adult clinic.

The questionnaire measured 5 knowledge skill sets—medical, educational/vocational, health benefits, social, and independent living—as well as 3 psychological assessments—feelings, stress, and self-efficacy.

To test how effective the questionnaire can be, Amy Sobota, MD, of Boston Medical Center, and her colleagues looked at the answers provided by 33 patients between the ages of 18 and 22.

Most respondents had good medical knowledge of SCD. Ninety-seven percent said they could explain SCD to another person and understood “how they got” the disease.

Ninety-four percent of patients also understood that SCD might be passed on to their children, and 71% of women said they knew how SCD could affect their pregnancy. However, only 30% of patients reported knowing what their baseline hemoglobin level is.

Likewise, the questionnaire suggested some knowledge gaps with regard to health benefits. Sixty-four percent of patients said they understood the various types of health insurance available to them, and 61% knew how their age could affect their health benefits.

Patients’ educational/vocational knowledge and capabilities were promising overall. Ninety-one percent of patients said they had a specific plan for the future, and 94% said they knew the education or employment required for their job choice. Seventy-six percent said they could identify the type of work that could cause problems related to SCD.

As for independent living, 91% of patients said they could fill their prescriptions on their own, 85% could make doctor’s appointments on their own, and 79% reported going to doctor’s appointments on their own.

With regard to social support, 97% of patients said they had a good social support system. But fewer (70%) had friends they could talk to about SCD, and only 48% knew about community-based SCD programs.

Most patients said they were worried that SCD would hinder them in some ways. Seventy-six percent worried about SCD getting in the way of school or work, and 51% worried it might prevent them from doing things they enjoy.

However, most patients felt sure they could function well. Eighty-eight percent said they could keep doing most of the things they do day-to-day, and 54% said they had ways of managing their pain without medication.

A minority of patients were worried or anxious about transitioning to adult care. Twenty-five percent were “quite a bit” or “extremely” worried, and 9% were similarly anxious about the transition. Sixteen percent said they felt “not at all” or “a little bit” all right to transition to an adult health care setting.

“Our study indicates that this assessment tool—the only one of its kind—provides important information to physicians of patients with sickle cell disease who are transitioning from pediatric to adult care,” Dr Sobota said. “Caregivers can use this information from patients in order to effectively tailor and guide their treatment and education through this transition.”

Saccharomyces cerevisiae

yeast buds before dividing

Credit: Carolyn Larabell

Research conducted in yeast suggests ribosomopathies are caused by a sequence of mistakes at the molecular level.

First, a genetic mutation prompts the production of defective ribosomes.

Then, a quality-control system eliminates most of these faulty ribosomes. This leaves few available for cells to produce required proteins, which causes anemia and bone marrow failure.

Next, a second mutation suppresses the quality-control system, making more ribosomes available to cells. However, these ribosomes are defective and cause changes in gene expression patterns that can result in cancer.

Jonathan Dinman, PhD, of the University of Maryland, and his colleagues described this chain of events in Proceedings of the National Academy of Sciences.

The researchers set out to investigate the structural, biochemical, and other defects in ribosomes that may lead to cancer. They selected budding yeast as their model system, as the assembly of its ribosomes shares many characteristics with human cells.

The team used the rpL10-R98S (uL16-R98S) mutant yeast model of the most commonly identified ribosomal mutation in T-cell acute lymphoblastic leukemia (T-ALL). They showed that the rpl10-R98S mutation causes a late-stage 60S subunit maturation failure that targets mutant ribosomes for degradation (the quality-control system).

When the researchers grew the mutant yeast cells on a petri dish, the cells grew very slowly. The team suggested that, because of the cells’ quality-control system, the majority of defective ribosomes carrying the T-ALL mutation do not “pass inspection.”

This severely limits the supply of ribosomes available to produce proteins, only providing enough ribosomes for cells to barely survive. This supply-and-demand problem hits rapidly dividing cells like blood cells particularly hard, and can therefore cause anemia and bone marrow failure in humans.

The bone marrow cells are subjected to selective pressure, an evolutionary process that favors the reproduction of things that resolve problems limiting their ability to thrive. In this case, cells would be favored that could circumvent the rpl10-R98S mutation.

After a few weeks, a group of fast-growing cells appeared on the petri dish containing the rpl10-R98S mutant yeast cells. The researchers sequenced the genomes of these cells and found a mutation in a second gene, NMD3, which suppresses the growth and ribosome biogenesis defects of rpl10-R98S cells.

So the mutation, NMD3-Y379D, increased the total number of ribosomes available to the cells, enabling cells with the mutation to make more protein, grow quickly, and take over the population. However, the available ribosomes were still defective.

NMD3-Y379D did not suppress the structural, biochemical, and translational fidelity defects of rpL10-R98S ribosomes. And the translational defects affected telomere maintenance. The mutant cells exhibited shortened telomeres, which have been linked to cancer.

The researchers proposed 2 different, but not mutually exclusive, explanations for these effects. The rpL10-R98S ribosomes could be directly changing patterns of gene expression and promoting T-ALL, and/or NMD3-Y379D could be driving T-ALL.

“Our yeast work has established a new paradigm that we are now translating to humans,” Dr Dinman said. “Once we determine which ribosomal mutations suppress the quality-control system in humans, we may be able to identify a potential drug target.”

Saccharomyces cerevisiae

yeast buds before dividing

Credit: Carolyn Larabell

Research conducted in yeast suggests ribosomopathies are caused by a sequence of mistakes at the molecular level.

First, a genetic mutation prompts the production of defective ribosomes.

Then, a quality-control system eliminates most of these faulty ribosomes. This leaves few available for cells to produce required proteins, which causes anemia and bone marrow failure.

Next, a second mutation suppresses the quality-control system, making more ribosomes available to cells. However, these ribosomes are defective and cause changes in gene expression patterns that can result in cancer.

Jonathan Dinman, PhD, of the University of Maryland, and his colleagues described this chain of events in Proceedings of the National Academy of Sciences.

The researchers set out to investigate the structural, biochemical, and other defects in ribosomes that may lead to cancer. They selected budding yeast as their model system, as the assembly of its ribosomes shares many characteristics with human cells.

The team used the rpL10-R98S (uL16-R98S) mutant yeast model of the most commonly identified ribosomal mutation in T-cell acute lymphoblastic leukemia (T-ALL). They showed that the rpl10-R98S mutation causes a late-stage 60S subunit maturation failure that targets mutant ribosomes for degradation (the quality-control system).

When the researchers grew the mutant yeast cells on a petri dish, the cells grew very slowly. The team suggested that, because of the cells’ quality-control system, the majority of defective ribosomes carrying the T-ALL mutation do not “pass inspection.”

This severely limits the supply of ribosomes available to produce proteins, only providing enough ribosomes for cells to barely survive. This supply-and-demand problem hits rapidly dividing cells like blood cells particularly hard, and can therefore cause anemia and bone marrow failure in humans.

The bone marrow cells are subjected to selective pressure, an evolutionary process that favors the reproduction of things that resolve problems limiting their ability to thrive. In this case, cells would be favored that could circumvent the rpl10-R98S mutation.

After a few weeks, a group of fast-growing cells appeared on the petri dish containing the rpl10-R98S mutant yeast cells. The researchers sequenced the genomes of these cells and found a mutation in a second gene, NMD3, which suppresses the growth and ribosome biogenesis defects of rpl10-R98S cells.

So the mutation, NMD3-Y379D, increased the total number of ribosomes available to the cells, enabling cells with the mutation to make more protein, grow quickly, and take over the population. However, the available ribosomes were still defective.

NMD3-Y379D did not suppress the structural, biochemical, and translational fidelity defects of rpL10-R98S ribosomes. And the translational defects affected telomere maintenance. The mutant cells exhibited shortened telomeres, which have been linked to cancer.

The researchers proposed 2 different, but not mutually exclusive, explanations for these effects. The rpL10-R98S ribosomes could be directly changing patterns of gene expression and promoting T-ALL, and/or NMD3-Y379D could be driving T-ALL.

“Our yeast work has established a new paradigm that we are now translating to humans,” Dr Dinman said. “Once we determine which ribosomal mutations suppress the quality-control system in humans, we may be able to identify a potential drug target.”

Saccharomyces cerevisiae

yeast buds before dividing

Credit: Carolyn Larabell

Research conducted in yeast suggests ribosomopathies are caused by a sequence of mistakes at the molecular level.

First, a genetic mutation prompts the production of defective ribosomes.

Then, a quality-control system eliminates most of these faulty ribosomes. This leaves few available for cells to produce required proteins, which causes anemia and bone marrow failure.

Next, a second mutation suppresses the quality-control system, making more ribosomes available to cells. However, these ribosomes are defective and cause changes in gene expression patterns that can result in cancer.

Jonathan Dinman, PhD, of the University of Maryland, and his colleagues described this chain of events in Proceedings of the National Academy of Sciences.

The researchers set out to investigate the structural, biochemical, and other defects in ribosomes that may lead to cancer. They selected budding yeast as their model system, as the assembly of its ribosomes shares many characteristics with human cells.

The team used the rpL10-R98S (uL16-R98S) mutant yeast model of the most commonly identified ribosomal mutation in T-cell acute lymphoblastic leukemia (T-ALL). They showed that the rpl10-R98S mutation causes a late-stage 60S subunit maturation failure that targets mutant ribosomes for degradation (the quality-control system).

When the researchers grew the mutant yeast cells on a petri dish, the cells grew very slowly. The team suggested that, because of the cells’ quality-control system, the majority of defective ribosomes carrying the T-ALL mutation do not “pass inspection.”

This severely limits the supply of ribosomes available to produce proteins, only providing enough ribosomes for cells to barely survive. This supply-and-demand problem hits rapidly dividing cells like blood cells particularly hard, and can therefore cause anemia and bone marrow failure in humans.

The bone marrow cells are subjected to selective pressure, an evolutionary process that favors the reproduction of things that resolve problems limiting their ability to thrive. In this case, cells would be favored that could circumvent the rpl10-R98S mutation.

After a few weeks, a group of fast-growing cells appeared on the petri dish containing the rpl10-R98S mutant yeast cells. The researchers sequenced the genomes of these cells and found a mutation in a second gene, NMD3, which suppresses the growth and ribosome biogenesis defects of rpl10-R98S cells.

So the mutation, NMD3-Y379D, increased the total number of ribosomes available to the cells, enabling cells with the mutation to make more protein, grow quickly, and take over the population. However, the available ribosomes were still defective.

NMD3-Y379D did not suppress the structural, biochemical, and translational fidelity defects of rpL10-R98S ribosomes. And the translational defects affected telomere maintenance. The mutant cells exhibited shortened telomeres, which have been linked to cancer.

The researchers proposed 2 different, but not mutually exclusive, explanations for these effects. The rpL10-R98S ribosomes could be directly changing patterns of gene expression and promoting T-ALL, and/or NMD3-Y379D could be driving T-ALL.

“Our yeast work has established a new paradigm that we are now translating to humans,” Dr Dinman said. “Once we determine which ribosomal mutations suppress the quality-control system in humans, we may be able to identify a potential drug target.”

DNA helices

Credit: NIGMS

NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).

Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.

The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.

This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.

“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”

Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.

He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.

The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.

According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.

For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.

Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.

SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.

The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.

The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.

DNA helices

Credit: NIGMS

NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).

Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.

The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.

This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.

“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”

Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.

He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.

The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.

According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.

For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.

Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.

SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.

The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.

The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.

DNA helices

Credit: NIGMS

NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).

Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.

The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.

This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.

“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”

Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.

He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.

The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.

According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.

For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.

Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.

SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.

The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.

The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.

Lone star tick

Credit: CDC

Health officials have reported 6 new cases of Heartland virus disease—5 in Missouri and 1 in Tennessee.

These cases, discovered in 2012 and 2013, add to the 2 cases discovered in 2009 and are described in the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report.

The Heartland virus was first reported in 2 farmers in northwestern Missouri who were hospitalized in 2009 with what was thought to be ehrlichiosis, a tick-borne disease.

However, the patients failed to improve with treatment, and testing failed to confirm ehlrlichiosis.

Working with state and local partners, the CDC eventually identified the cause of the men’s illness: a previously unknown phlebovirus, now dubbed the Heartland virus.

Although we do not know for certain how patients are infected with the virus, research has suggested that ticks, namely lone star ticks, transmit it.

Ongoing investigations have uncovered 6 more cases of Heartland virus disease. All of the patients were white men older than 50 years of age. Five of them reported tick bites in the days or weeks before they fell ill.

Their symptoms started in May to September and included fever, fatigue, loss of appetite, headache, nausea, and muscle pain. The patients also had leukopenia and thrombocytopenia.

Four of the 6 patients were hospitalized. And 1 man, who suffered from other health conditions, died. It is not known if the Heartland virus was the cause of death or how much it contributed to his death.

The CDC has been working with the Missouri and Tennessee state health departments and other federal agencies to advance our understanding of Heartland virus disease by learning more about the patients who were infected, their illness, and their exposure to ticks.

The CDC aims to determine the symptoms and severity of the disease, where it is found, how people are being infected, and how to prevent infections.

CDC studies to date have shown that the Heartland virus is carried by lone star ticks, which are primarily found in the southeastern and eastern US.

Researchers hope additional studies can confirm whether ticks can spread the virus and reveal which other insects or animals may be involved in the transmission cycle. The CDC is also looking for the Heartland virus in other parts of the country to understand how widely it may be distributed.

“During the past 2 years, CDC has worked closely with state health departments, hospitals, and many experts from universities and other federal agencies to learn more about Heartland virus,” said Roger Nasci, PhD, chief of the CDC’s Arboviral Diseases Branch.

“By gathering information about the disease Heartland virus causes, and about how it’s spread to people, we hope to better understand the potential impact on the public’s health and how we can help protect people from this virus.”

The CDC developed the blood tests used to confirm the new cases of Heartland virus disease. CDC teams are working to further validate these tests and develop additional tests. The researchers hope to develop a diagnostic test that public health laboratories could use to test for the virus.

There is no specific treatment or vaccine for Heartland virus disease. However, supportive therapies such as intravenous fluids and fever reducers can relieve some symptoms of Heartland disease.

To reduce the risk of Heartland and other vector-borne diseases, the CDC recommends:

• Avoiding wooded and bushy areas with high grass and leaf litter
• Using insect repellent when outdoors
• Using products that contain permethrin on clothing
• Conducting a full-body tick check after spending time outdoors
• Bathing as soon as possible after coming indoors to wash off and more easily find any ticks
• Examining gear and pets, as ticks can “ride” into the home and attach to a person later.

For more information on the Heartland virus, visit the CDC website.

Lone star tick

Credit: CDC

Health officials have reported 6 new cases of Heartland virus disease—5 in Missouri and 1 in Tennessee.

These cases, discovered in 2012 and 2013, add to the 2 cases discovered in 2009 and are described in the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report.

The Heartland virus was first reported in 2 farmers in northwestern Missouri who were hospitalized in 2009 with what was thought to be ehrlichiosis, a tick-borne disease.

However, the patients failed to improve with treatment, and testing failed to confirm ehlrlichiosis.

Working with state and local partners, the CDC eventually identified the cause of the men’s illness: a previously unknown phlebovirus, now dubbed the Heartland virus.

Although we do not know for certain how patients are infected with the virus, research has suggested that ticks, namely lone star ticks, transmit it.

Ongoing investigations have uncovered 6 more cases of Heartland virus disease. All of the patients were white men older than 50 years of age. Five of them reported tick bites in the days or weeks before they fell ill.

Their symptoms started in May to September and included fever, fatigue, loss of appetite, headache, nausea, and muscle pain. The patients also had leukopenia and thrombocytopenia.

Four of the 6 patients were hospitalized. And 1 man, who suffered from other health conditions, died. It is not known if the Heartland virus was the cause of death or how much it contributed to his death.

The CDC has been working with the Missouri and Tennessee state health departments and other federal agencies to advance our understanding of Heartland virus disease by learning more about the patients who were infected, their illness, and their exposure to ticks.

The CDC aims to determine the symptoms and severity of the disease, where it is found, how people are being infected, and how to prevent infections.

CDC studies to date have shown that the Heartland virus is carried by lone star ticks, which are primarily found in the southeastern and eastern US.

Researchers hope additional studies can confirm whether ticks can spread the virus and reveal which other insects or animals may be involved in the transmission cycle. The CDC is also looking for the Heartland virus in other parts of the country to understand how widely it may be distributed.

“During the past 2 years, CDC has worked closely with state health departments, hospitals, and many experts from universities and other federal agencies to learn more about Heartland virus,” said Roger Nasci, PhD, chief of the CDC’s Arboviral Diseases Branch.

“By gathering information about the disease Heartland virus causes, and about how it’s spread to people, we hope to better understand the potential impact on the public’s health and how we can help protect people from this virus.”

The CDC developed the blood tests used to confirm the new cases of Heartland virus disease. CDC teams are working to further validate these tests and develop additional tests. The researchers hope to develop a diagnostic test that public health laboratories could use to test for the virus.

There is no specific treatment or vaccine for Heartland virus disease. However, supportive therapies such as intravenous fluids and fever reducers can relieve some symptoms of Heartland disease.

To reduce the risk of Heartland and other vector-borne diseases, the CDC recommends:

• Avoiding wooded and bushy areas with high grass and leaf litter
• Using insect repellent when outdoors
• Using products that contain permethrin on clothing
• Conducting a full-body tick check after spending time outdoors
• Bathing as soon as possible after coming indoors to wash off and more easily find any ticks
• Examining gear and pets, as ticks can “ride” into the home and attach to a person later.

For more information on the Heartland virus, visit the CDC website.

Lone star tick

Credit: CDC

Health officials have reported 6 new cases of Heartland virus disease—5 in Missouri and 1 in Tennessee.

These cases, discovered in 2012 and 2013, add to the 2 cases discovered in 2009 and are described in the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report.

The Heartland virus was first reported in 2 farmers in northwestern Missouri who were hospitalized in 2009 with what was thought to be ehrlichiosis, a tick-borne disease.

However, the patients failed to improve with treatment, and testing failed to confirm ehlrlichiosis.

Working with state and local partners, the CDC eventually identified the cause of the men’s illness: a previously unknown phlebovirus, now dubbed the Heartland virus.

Although we do not know for certain how patients are infected with the virus, research has suggested that ticks, namely lone star ticks, transmit it.

Ongoing investigations have uncovered 6 more cases of Heartland virus disease. All of the patients were white men older than 50 years of age. Five of them reported tick bites in the days or weeks before they fell ill.

Their symptoms started in May to September and included fever, fatigue, loss of appetite, headache, nausea, and muscle pain. The patients also had leukopenia and thrombocytopenia.

Four of the 6 patients were hospitalized. And 1 man, who suffered from other health conditions, died. It is not known if the Heartland virus was the cause of death or how much it contributed to his death.

The CDC has been working with the Missouri and Tennessee state health departments and other federal agencies to advance our understanding of Heartland virus disease by learning more about the patients who were infected, their illness, and their exposure to ticks.

The CDC aims to determine the symptoms and severity of the disease, where it is found, how people are being infected, and how to prevent infections.

CDC studies to date have shown that the Heartland virus is carried by lone star ticks, which are primarily found in the southeastern and eastern US.

Researchers hope additional studies can confirm whether ticks can spread the virus and reveal which other insects or animals may be involved in the transmission cycle. The CDC is also looking for the Heartland virus in other parts of the country to understand how widely it may be distributed.

“During the past 2 years, CDC has worked closely with state health departments, hospitals, and many experts from universities and other federal agencies to learn more about Heartland virus,” said Roger Nasci, PhD, chief of the CDC’s Arboviral Diseases Branch.

“By gathering information about the disease Heartland virus causes, and about how it’s spread to people, we hope to better understand the potential impact on the public’s health and how we can help protect people from this virus.”

The CDC developed the blood tests used to confirm the new cases of Heartland virus disease. CDC teams are working to further validate these tests and develop additional tests. The researchers hope to develop a diagnostic test that public health laboratories could use to test for the virus.

There is no specific treatment or vaccine for Heartland virus disease. However, supportive therapies such as intravenous fluids and fever reducers can relieve some symptoms of Heartland disease.

To reduce the risk of Heartland and other vector-borne diseases, the CDC recommends:

• Avoiding wooded and bushy areas with high grass and leaf litter
• Using insect repellent when outdoors
• Using products that contain permethrin on clothing
• Conducting a full-body tick check after spending time outdoors
• Bathing as soon as possible after coming indoors to wash off and more easily find any ticks
• Examining gear and pets, as ticks can “ride” into the home and attach to a person later.

For more information on the Heartland virus, visit the CDC website.

Red blood cells

Credit: NHLBI

Results of preclinical research could aid the development of new treatments for hemolysis, which may have implications for patients with sickle cell anemia and those who receive blood transfusions.

The researchers were investigating the possibility of using haptoglobin to prevent the chemical reactions triggered by hemoglobin after hemolysis.

Haptoglobin is known to bind acellular adult hemoglobin dimers and facilitate their clearance after hemolysis.

But haptoglobin exists in different forms. The 3 main phenotypes—Hp1-1, Hp2-1, and Hp2-2—have diverse structural configurations, and previous research suggested they have different biological activities.

With the current study, however, the researchers showed the different forms of haptoglobin actually exhibit similar activity.

Todd L. Mollan, PhD, of the Center for Biologics Evaluation and Research at the Food and Drug Administration in Bethesda, Maryland, and his colleagues presented these findings in Free Radical Biology and Medicine.

The researchers studied hemoglobin dimers in complex with unfractionated haptoglobin (a mixture of Hp1-1, Hp2-1, and Hp2-2); fractionated, dimeric haptoglobin (Hp1-1); and fractionated, polymeric haptoglobin (predominantly Hp2-2, with minor amounts of Hp2-1).

The team also complexed ferrous and ferric hemoglobins with unfractionated haptoglobin and its fractionated forms.

Experiments revealed no significant differences among the different complexes with regard to hemoglobin-haptoglobin binding kinetics, hydrogen-peroxide-driven oxidative transitions of the heme iron, radical formation, heme loss, or intrinsic redox potential.

The researchers said these results should be taken into account when designing phenotype-specific haptoglobin therapies.

Red blood cells

Credit: NHLBI

Results of preclinical research could aid the development of new treatments for hemolysis, which may have implications for patients with sickle cell anemia and those who receive blood transfusions.

The researchers were investigating the possibility of using haptoglobin to prevent the chemical reactions triggered by hemoglobin after hemolysis.

Haptoglobin is known to bind acellular adult hemoglobin dimers and facilitate their clearance after hemolysis.

But haptoglobin exists in different forms. The 3 main phenotypes—Hp1-1, Hp2-1, and Hp2-2—have diverse structural configurations, and previous research suggested they have different biological activities.

With the current study, however, the researchers showed the different forms of haptoglobin actually exhibit similar activity.

Todd L. Mollan, PhD, of the Center for Biologics Evaluation and Research at the Food and Drug Administration in Bethesda, Maryland, and his colleagues presented these findings in Free Radical Biology and Medicine.

The researchers studied hemoglobin dimers in complex with unfractionated haptoglobin (a mixture of Hp1-1, Hp2-1, and Hp2-2); fractionated, dimeric haptoglobin (Hp1-1); and fractionated, polymeric haptoglobin (predominantly Hp2-2, with minor amounts of Hp2-1).

The team also complexed ferrous and ferric hemoglobins with unfractionated haptoglobin and its fractionated forms.

Experiments revealed no significant differences among the different complexes with regard to hemoglobin-haptoglobin binding kinetics, hydrogen-peroxide-driven oxidative transitions of the heme iron, radical formation, heme loss, or intrinsic redox potential.

The researchers said these results should be taken into account when designing phenotype-specific haptoglobin therapies.

Red blood cells

Credit: NHLBI

Results of preclinical research could aid the development of new treatments for hemolysis, which may have implications for patients with sickle cell anemia and those who receive blood transfusions.

The researchers were investigating the possibility of using haptoglobin to prevent the chemical reactions triggered by hemoglobin after hemolysis.

Haptoglobin is known to bind acellular adult hemoglobin dimers and facilitate their clearance after hemolysis.

But haptoglobin exists in different forms. The 3 main phenotypes—Hp1-1, Hp2-1, and Hp2-2—have diverse structural configurations, and previous research suggested they have different biological activities.

With the current study, however, the researchers showed the different forms of haptoglobin actually exhibit similar activity.

Todd L. Mollan, PhD, of the Center for Biologics Evaluation and Research at the Food and Drug Administration in Bethesda, Maryland, and his colleagues presented these findings in Free Radical Biology and Medicine.

The researchers studied hemoglobin dimers in complex with unfractionated haptoglobin (a mixture of Hp1-1, Hp2-1, and Hp2-2); fractionated, dimeric haptoglobin (Hp1-1); and fractionated, polymeric haptoglobin (predominantly Hp2-2, with minor amounts of Hp2-1).

The team also complexed ferrous and ferric hemoglobins with unfractionated haptoglobin and its fractionated forms.

Experiments revealed no significant differences among the different complexes with regard to hemoglobin-haptoglobin binding kinetics, hydrogen-peroxide-driven oxidative transitions of the heme iron, radical formation, heme loss, or intrinsic redox potential.

The researchers said these results should be taken into account when designing phenotype-specific haptoglobin therapies.

Tohru Ikuta, MD, PhD

Medical College of Georgia

Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.

The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.

The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.

The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.

To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.

The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.

“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”

When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.

And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.

They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.

These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.

“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”

Tohru Ikuta, MD, PhD

Medical College of Georgia

Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.

The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.

The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.

The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.

To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.

The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.

“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”

When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.

And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.

They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.

These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.

“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”

Tohru Ikuta, MD, PhD

Medical College of Georgia

Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.

The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.

The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.

The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.

To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.

The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.

“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”

When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.

And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.

They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.

These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.

“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Drugs in vials

Credit: Bill Branson

The UK’s National Institute for Health and Care Excellence (NICE) has asked the manufacturer of eculizumab (Soliris) to explain the high cost of the drug.

Research has suggested that eculizumab can be effective against atypical hemolytic uremic syndrome (aHUS), a rare disease that often proves difficult to treat.

So the National Health Service (NHS) has made eculizumab available for these patients on an interim basis, pending NICE appraisal.

However, an advisory committee for NICE has estimated that routine use of eculizumab would cost the NHS about £58 million in the first year, and costs would exceed £80 million in 5 years.

Therefore, in its draft guidance for eculizumab, the committee has asked the drug’s manufacturer, Alexion Pharma, to explain its costs.

“[The committee has] asked for clarification from the company on aspects of the manufacturing, research, and development costs of a medicinal product for the treatment of a very rare condition,” said Sir Andrew Dillon, Chief Executive at NICE.

“It has also asked NHS England for clarification on treatment costs for a highly specialized technology in the context of a highly specialized service. The information provided will be considered at the next meeting of the evaluation committee in April.”

The committee will also consider comments on its draft guidance at the meeting. The guidance is available for public comment until midday on March 25.

About aHUS

Estimated to affect more than 200 people in England, aHUS is a chronic condition that causes severe inflammation of blood vessels and thrombus formation in small blood vessels throughout the body.

Patients with aHUS can experience significant kidney impairment, thrombosis, heart failure, and brain injury. In about 70% of patients, aHUS is associated with an underlying genetic or acquired abnormality of proteins in the complement immune system.

Before eculizumab became available, plasma therapy (infusion and/or exchange) was the main treatment for aHUS. However, not all patients with aHUS respond to plasma therapy. And up to 40% of patients may die or progress to end-stage renal failure and require dialysis with the first clinical aHUS manifestation, despite the use of plasma therapy.

Some patients may be eligible for a kidney or combined kidney-liver transplantation. However, there is a high risk of organ rejection following recurrent disease.

Eculizumab in aHUS: Treatment and cost

Eculizumab inhibits the disease process by blocking pro-thrombotic and pro-inflammatory processes that can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5 and then every 12 to 16 days. The summary of product characteristics for eculizumab states that treatment should be continued for the patient’s lifetime, unless discontinuation is clinically indicated.

Eculizumab costs £3150 per 30 mL vial, excluding tax, according to the British National Formulary.

“Alexion insisted that its information about the overall cost of eculizumab be kept confidential, and so NICE is unable to share these details of the Alexion submission with stakeholders,” Dillon said.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an estimate of the possible budget impact eculizumab might have, using information available in the public domain.

This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

Assuming all of these patients receive eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million), the budget impact will rise to £62.5 million. That is assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients).

Drugs in vials

Credit: Bill Branson

The UK’s National Institute for Health and Care Excellence (NICE) has asked the manufacturer of eculizumab (Soliris) to explain the high cost of the drug.

Research has suggested that eculizumab can be effective against atypical hemolytic uremic syndrome (aHUS), a rare disease that often proves difficult to treat.

So the National Health Service (NHS) has made eculizumab available for these patients on an interim basis, pending NICE appraisal.

However, an advisory committee for NICE has estimated that routine use of eculizumab would cost the NHS about £58 million in the first year, and costs would exceed £80 million in 5 years.

Therefore, in its draft guidance for eculizumab, the committee has asked the drug’s manufacturer, Alexion Pharma, to explain its costs.

“[The committee has] asked for clarification from the company on aspects of the manufacturing, research, and development costs of a medicinal product for the treatment of a very rare condition,” said Sir Andrew Dillon, Chief Executive at NICE.

“It has also asked NHS England for clarification on treatment costs for a highly specialized technology in the context of a highly specialized service. The information provided will be considered at the next meeting of the evaluation committee in April.”

The committee will also consider comments on its draft guidance at the meeting. The guidance is available for public comment until midday on March 25.

About aHUS

Estimated to affect more than 200 people in England, aHUS is a chronic condition that causes severe inflammation of blood vessels and thrombus formation in small blood vessels throughout the body.

Patients with aHUS can experience significant kidney impairment, thrombosis, heart failure, and brain injury. In about 70% of patients, aHUS is associated with an underlying genetic or acquired abnormality of proteins in the complement immune system.

Before eculizumab became available, plasma therapy (infusion and/or exchange) was the main treatment for aHUS. However, not all patients with aHUS respond to plasma therapy. And up to 40% of patients may die or progress to end-stage renal failure and require dialysis with the first clinical aHUS manifestation, despite the use of plasma therapy.

Some patients may be eligible for a kidney or combined kidney-liver transplantation. However, there is a high risk of organ rejection following recurrent disease.

Eculizumab in aHUS: Treatment and cost

Eculizumab inhibits the disease process by blocking pro-thrombotic and pro-inflammatory processes that can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5 and then every 12 to 16 days. The summary of product characteristics for eculizumab states that treatment should be continued for the patient’s lifetime, unless discontinuation is clinically indicated.

Eculizumab costs £3150 per 30 mL vial, excluding tax, according to the British National Formulary.

“Alexion insisted that its information about the overall cost of eculizumab be kept confidential, and so NICE is unable to share these details of the Alexion submission with stakeholders,” Dillon said.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an estimate of the possible budget impact eculizumab might have, using information available in the public domain.

This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

Assuming all of these patients receive eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million), the budget impact will rise to £62.5 million. That is assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients).

Drugs in vials

Credit: Bill Branson

The UK’s National Institute for Health and Care Excellence (NICE) has asked the manufacturer of eculizumab (Soliris) to explain the high cost of the drug.

Research has suggested that eculizumab can be effective against atypical hemolytic uremic syndrome (aHUS), a rare disease that often proves difficult to treat.

So the National Health Service (NHS) has made eculizumab available for these patients on an interim basis, pending NICE appraisal.

However, an advisory committee for NICE has estimated that routine use of eculizumab would cost the NHS about £58 million in the first year, and costs would exceed £80 million in 5 years.

Therefore, in its draft guidance for eculizumab, the committee has asked the drug’s manufacturer, Alexion Pharma, to explain its costs.

“[The committee has] asked for clarification from the company on aspects of the manufacturing, research, and development costs of a medicinal product for the treatment of a very rare condition,” said Sir Andrew Dillon, Chief Executive at NICE.

“It has also asked NHS England for clarification on treatment costs for a highly specialized technology in the context of a highly specialized service. The information provided will be considered at the next meeting of the evaluation committee in April.”

The committee will also consider comments on its draft guidance at the meeting. The guidance is available for public comment until midday on March 25.

About aHUS

Estimated to affect more than 200 people in England, aHUS is a chronic condition that causes severe inflammation of blood vessels and thrombus formation in small blood vessels throughout the body.

Patients with aHUS can experience significant kidney impairment, thrombosis, heart failure, and brain injury. In about 70% of patients, aHUS is associated with an underlying genetic or acquired abnormality of proteins in the complement immune system.

Before eculizumab became available, plasma therapy (infusion and/or exchange) was the main treatment for aHUS. However, not all patients with aHUS respond to plasma therapy. And up to 40% of patients may die or progress to end-stage renal failure and require dialysis with the first clinical aHUS manifestation, despite the use of plasma therapy.

Some patients may be eligible for a kidney or combined kidney-liver transplantation. However, there is a high risk of organ rejection following recurrent disease.

Eculizumab in aHUS: Treatment and cost

Eculizumab inhibits the disease process by blocking pro-thrombotic and pro-inflammatory processes that can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5 and then every 12 to 16 days. The summary of product characteristics for eculizumab states that treatment should be continued for the patient’s lifetime, unless discontinuation is clinically indicated.

Eculizumab costs £3150 per 30 mL vial, excluding tax, according to the British National Formulary.

“Alexion insisted that its information about the overall cost of eculizumab be kept confidential, and so NICE is unable to share these details of the Alexion submission with stakeholders,” Dillon said.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an estimate of the possible budget impact eculizumab might have, using information available in the public domain.

This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

Assuming all of these patients receive eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million), the budget impact will rise to £62.5 million. That is assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients).

A sickled red blood cell

(right) and a normal one

Credit: Betty Pace

The American Thoracic Society has developed clinical practice guidelines to help clinicians identify and manage patients with sickle cell disease who are at an increased risk for mortality from pulmonary hypertension.

“With the development of new treatments, many patients with sickle cell disease are now surviving long enough to develop pulmonary hypertension, with an estimated prevalence of 6% to 11%,” said guideline author Elizabeth S. Klings, MD, of the Boston University School of Medicine in Massachusetts.

“Although pulmonary hypertension and elevated tricuspid jet velocity [TRV, an indicator of pulmonary hypertension measured by echocardiography] are both associated with an increased mortality risk, there is currently no standardized approach for identifying and managing these patients.”

So Dr Klings and her colleagues decided to offer some guidance. Their recommendations for managing these patients appear in the American Journal of Respiratory and Critical Care Medicine.

The guideline authors point out that clinicians can evaluate patient mortality noninvasively by measuring the TRV with Doppler echocardiography or by measuring serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) levels.

An invasive method is taking direct hemodynamic measurements via right heart catheterization (RHC).

An increased risk for mortality is defined as a TRV ≥ 2.5 m/second, an NT-pro-BNP level ≥ 160 pg/mL, or RHC-confirmed pulmonary hypertension.

Patients who meet these criteria should receive hydroxyurea. Patients who do not respond to or are not candidates for hydroxyurea treatment can be considered for chronic transfusion therapy.

For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional risk factors for hemorrhage, the guidelines recommend indefinite anticoagulant therapy rather than a limited duration of therapy.

Patients with elevated TRV alone or elevated NT-pro-BNP alone should not be treated with targeted pulmonary arterial hypertension therapies, including prostanoid, endothelin receptor antagonist, and phosphodiesterase-5 inhibitor therapy.

Most patients with RHC-confirmed pulmonary hypertension should not receive targeted therapy.

For select patents with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms, the guidelines suggest a trial of either a prostanoid or an endothelin receptor antagonist.

Patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms should not receive phosphodiesterase-5 inhibitor therapy as first-line treatment.

“Most of our current recommendations are limited by a lack of large-scale clinical trials in this population,” Dr Klings noted. “We need to continue our research efforts into this disease and its management to understand what the optimal treatment regimen for these patients is.”

“Management of patients with sickle cell disease with an increased risk for mortality and pulmonary hypertension will ultimately be a collaborative effort, including adult and pediatric pulmonologists, cardiologists, and hematologists.”

A sickled red blood cell

(right) and a normal one

Credit: Betty Pace

The American Thoracic Society has developed clinical practice guidelines to help clinicians identify and manage patients with sickle cell disease who are at an increased risk for mortality from pulmonary hypertension.

“With the development of new treatments, many patients with sickle cell disease are now surviving long enough to develop pulmonary hypertension, with an estimated prevalence of 6% to 11%,” said guideline author Elizabeth S. Klings, MD, of the Boston University School of Medicine in Massachusetts.

“Although pulmonary hypertension and elevated tricuspid jet velocity [TRV, an indicator of pulmonary hypertension measured by echocardiography] are both associated with an increased mortality risk, there is currently no standardized approach for identifying and managing these patients.”

So Dr Klings and her colleagues decided to offer some guidance. Their recommendations for managing these patients appear in the American Journal of Respiratory and Critical Care Medicine.

The guideline authors point out that clinicians can evaluate patient mortality noninvasively by measuring the TRV with Doppler echocardiography or by measuring serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) levels.

An invasive method is taking direct hemodynamic measurements via right heart catheterization (RHC).

An increased risk for mortality is defined as a TRV ≥ 2.5 m/second, an NT-pro-BNP level ≥ 160 pg/mL, or RHC-confirmed pulmonary hypertension.

Patients who meet these criteria should receive hydroxyurea. Patients who do not respond to or are not candidates for hydroxyurea treatment can be considered for chronic transfusion therapy.

For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional risk factors for hemorrhage, the guidelines recommend indefinite anticoagulant therapy rather than a limited duration of therapy.

Patients with elevated TRV alone or elevated NT-pro-BNP alone should not be treated with targeted pulmonary arterial hypertension therapies, including prostanoid, endothelin receptor antagonist, and phosphodiesterase-5 inhibitor therapy.

Most patients with RHC-confirmed pulmonary hypertension should not receive targeted therapy.

For select patents with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms, the guidelines suggest a trial of either a prostanoid or an endothelin receptor antagonist.

Patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms should not receive phosphodiesterase-5 inhibitor therapy as first-line treatment.

“Most of our current recommendations are limited by a lack of large-scale clinical trials in this population,” Dr Klings noted. “We need to continue our research efforts into this disease and its management to understand what the optimal treatment regimen for these patients is.”

“Management of patients with sickle cell disease with an increased risk for mortality and pulmonary hypertension will ultimately be a collaborative effort, including adult and pediatric pulmonologists, cardiologists, and hematologists.”

A sickled red blood cell

(right) and a normal one

Credit: Betty Pace

The American Thoracic Society has developed clinical practice guidelines to help clinicians identify and manage patients with sickle cell disease who are at an increased risk for mortality from pulmonary hypertension.

“With the development of new treatments, many patients with sickle cell disease are now surviving long enough to develop pulmonary hypertension, with an estimated prevalence of 6% to 11%,” said guideline author Elizabeth S. Klings, MD, of the Boston University School of Medicine in Massachusetts.

“Although pulmonary hypertension and elevated tricuspid jet velocity [TRV, an indicator of pulmonary hypertension measured by echocardiography] are both associated with an increased mortality risk, there is currently no standardized approach for identifying and managing these patients.”

So Dr Klings and her colleagues decided to offer some guidance. Their recommendations for managing these patients appear in the American Journal of Respiratory and Critical Care Medicine.

The guideline authors point out that clinicians can evaluate patient mortality noninvasively by measuring the TRV with Doppler echocardiography or by measuring serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) levels.

An invasive method is taking direct hemodynamic measurements via right heart catheterization (RHC).

An increased risk for mortality is defined as a TRV ≥ 2.5 m/second, an NT-pro-BNP level ≥ 160 pg/mL, or RHC-confirmed pulmonary hypertension.

Patients who meet these criteria should receive hydroxyurea. Patients who do not respond to or are not candidates for hydroxyurea treatment can be considered for chronic transfusion therapy.

For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional risk factors for hemorrhage, the guidelines recommend indefinite anticoagulant therapy rather than a limited duration of therapy.

Patients with elevated TRV alone or elevated NT-pro-BNP alone should not be treated with targeted pulmonary arterial hypertension therapies, including prostanoid, endothelin receptor antagonist, and phosphodiesterase-5 inhibitor therapy.

Most patients with RHC-confirmed pulmonary hypertension should not receive targeted therapy.

For select patents with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms, the guidelines suggest a trial of either a prostanoid or an endothelin receptor antagonist.

Patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms should not receive phosphodiesterase-5 inhibitor therapy as first-line treatment.

“Most of our current recommendations are limited by a lack of large-scale clinical trials in this population,” Dr Klings noted. “We need to continue our research efforts into this disease and its management to understand what the optimal treatment regimen for these patients is.”

“Management of patients with sickle cell disease with an increased risk for mortality and pulmonary hypertension will ultimately be a collaborative effort, including adult and pediatric pulmonologists, cardiologists, and hematologists.”