Anemia

la Santa Creu i Sant Pau

New research suggests that mutations in the RFWD3 gene cause Fanconi anemia (FA).

Investigators detected mutations in the RFWD3 gene in a child with FA and confirmed the relationship between the mutations and the disorder via functional studies in cell and animal models.

The team described this research in The Journal of Clinical Oncology.

Previously, there was knowledge of 21 genes involved in FA.

“The discovery of new genes is essential not only for genetic diagnosis and advice, but also for the development of new therapies,” said study author Jordi Surrallés, PhD, of the Hospital de la Santa Creu i Sant Pau and Universitat Autonoma de Barcelona in Spain.

“The RFWD3 protein is one of the few deficient proteins in patients with Fanconi anemia in which we can see a clear enzymatic activity (ubiquitin ligase), which opens the door to massive drug screenings. In this sense, my group has already worked on several screenings of thousands of therapeutic molecules with the aim of repositioning a drug for this disease.” 

la Santa Creu i Sant Pau

New research suggests that mutations in the RFWD3 gene cause Fanconi anemia (FA).

Investigators detected mutations in the RFWD3 gene in a child with FA and confirmed the relationship between the mutations and the disorder via functional studies in cell and animal models.

The team described this research in The Journal of Clinical Oncology.

Previously, there was knowledge of 21 genes involved in FA.

“The discovery of new genes is essential not only for genetic diagnosis and advice, but also for the development of new therapies,” said study author Jordi Surrallés, PhD, of the Hospital de la Santa Creu i Sant Pau and Universitat Autonoma de Barcelona in Spain.

“The RFWD3 protein is one of the few deficient proteins in patients with Fanconi anemia in which we can see a clear enzymatic activity (ubiquitin ligase), which opens the door to massive drug screenings. In this sense, my group has already worked on several screenings of thousands of therapeutic molecules with the aim of repositioning a drug for this disease.” 

la Santa Creu i Sant Pau

New research suggests that mutations in the RFWD3 gene cause Fanconi anemia (FA).

Investigators detected mutations in the RFWD3 gene in a child with FA and confirmed the relationship between the mutations and the disorder via functional studies in cell and animal models.

The team described this research in The Journal of Clinical Oncology.

Previously, there was knowledge of 21 genes involved in FA.

“The discovery of new genes is essential not only for genetic diagnosis and advice, but also for the development of new therapies,” said study author Jordi Surrallés, PhD, of the Hospital de la Santa Creu i Sant Pau and Universitat Autonoma de Barcelona in Spain.

“The RFWD3 protein is one of the few deficient proteins in patients with Fanconi anemia in which we can see a clear enzymatic activity (ubiquitin ligase), which opens the door to massive drug screenings. In this sense, my group has already worked on several screenings of thousands of therapeutic molecules with the aim of repositioning a drug for this disease.” 

Photo by Juan D. Alfonso

A pair of studies suggest physicians should consider testing female adolescents for iron deficiency within a few years of starting menses.

Women are typically tested for anemia in their teens, with a quick and affordable hemoglobin test.

However, iron deficiency can develop years before anemia and can be missed by hemoglobin testing alone.

Blood tests for iron deficiency without anemia are more costly and more difficult to obtain than hemoglobin testing for anemia.

Deepa Sekhar, MD, of Penn State College of Medicine in Hershey, Pennsylvania, and her colleagues set out to determine risk factors for iron deficiency without anemia in order to pinpoint which women could benefit most from the more costly testing.

The results of the researchers’ 2 studies were published in PLOS ONE and The Journal of Pediatrics.

PLOS ONE study

The researchers evaluated data from 6216 females, ages 12 to 49, who took part in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2010. As part of the survey, participants were tested for both iron deficiency and anemia.

Eight percent of all subjects (n=494) had iron deficiency.

Nine percent (n=250) of non-anemic younger women (ages 12-21) had iron deficiency, as did 7% (n=244) of older women (ages 22-49) who were not anemic.

The researchers looked at potential risk factors for iron deficiency, including the age when women started menstruating, as well as their race/ethnicity, poverty status, food insecurity, tobacco or nicotine use, dietary information, body mass index, and physical activity.

All of these factors have been associated with iron-deficiency anemia in women in prior studies.

In this study, there was only 1 risk factor significantly associated with iron deficiency without anemia.

Young women (ages 12-21) who had been menstruating for more than 3 years had a significantly higher risk of iron deficiency without anemia (risk ratio=3.18).

The Journal of Pediatrics study

In this study, the researchers looked at whether a questionnaire could better predict iron status.

The questionnaire included questions on depression, poor attention, and daytime sleepiness, all of which have been associated with iron deficiency or iron-deficiency anemia, but were not captured in the prior NHANES analyses.

This questionnaire was compared to the 4 questions assessing iron-deficiency anemia risk in the Bright Futures Adolescent Previsit Questionnaire, a survey recommended for physician use by the American Academy of Pediatrics.

Ninety-six female adolescents participated in this study. Eighteen percent of them (n=17) had iron deficiency, and 5% (n=5) had iron-deficiency anemia.

Both the Bright Futures questions and the researchers’ risk assessment questionnaire poorly predicted ferritin and hemoglobin values in these subjects.

Mean differences in depression, poor attention, food insecurity, daytime sleepiness, and body mass index percentile were not significantly associated with ferritin or hemoglobin.

Conclusions

The results of these 2 studies suggest that risk factors and assessments cannot accurately determine which young women should receive testing for iron deficiency, although results from the first study might be used to determine when testing should occur.

“I think we need to establish the optimal timing for an objective assessment of adolescent iron deficiency and anemia,” Dr Sekhar said.

She believes the appropriate age may be 16 years old, when most females will have been menstruating for at least 3 years.

Further research will be needed to determine which blood test for iron deficiency without anemia is accurate, cost-efficient, and practical for routine doctor’s office use.

This test should be given with hemoglobin testing to catch all young women on the spectrum of iron deficiency, Dr Sekhar said.

Photo by Juan D. Alfonso

A pair of studies suggest physicians should consider testing female adolescents for iron deficiency within a few years of starting menses.

Women are typically tested for anemia in their teens, with a quick and affordable hemoglobin test.

However, iron deficiency can develop years before anemia and can be missed by hemoglobin testing alone.

Blood tests for iron deficiency without anemia are more costly and more difficult to obtain than hemoglobin testing for anemia.

Deepa Sekhar, MD, of Penn State College of Medicine in Hershey, Pennsylvania, and her colleagues set out to determine risk factors for iron deficiency without anemia in order to pinpoint which women could benefit most from the more costly testing.

The results of the researchers’ 2 studies were published in PLOS ONE and The Journal of Pediatrics.

PLOS ONE study

The researchers evaluated data from 6216 females, ages 12 to 49, who took part in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2010. As part of the survey, participants were tested for both iron deficiency and anemia.

Eight percent of all subjects (n=494) had iron deficiency.

Nine percent (n=250) of non-anemic younger women (ages 12-21) had iron deficiency, as did 7% (n=244) of older women (ages 22-49) who were not anemic.

The researchers looked at potential risk factors for iron deficiency, including the age when women started menstruating, as well as their race/ethnicity, poverty status, food insecurity, tobacco or nicotine use, dietary information, body mass index, and physical activity.

All of these factors have been associated with iron-deficiency anemia in women in prior studies.

In this study, there was only 1 risk factor significantly associated with iron deficiency without anemia.

Young women (ages 12-21) who had been menstruating for more than 3 years had a significantly higher risk of iron deficiency without anemia (risk ratio=3.18).

The Journal of Pediatrics study

In this study, the researchers looked at whether a questionnaire could better predict iron status.

The questionnaire included questions on depression, poor attention, and daytime sleepiness, all of which have been associated with iron deficiency or iron-deficiency anemia, but were not captured in the prior NHANES analyses.

This questionnaire was compared to the 4 questions assessing iron-deficiency anemia risk in the Bright Futures Adolescent Previsit Questionnaire, a survey recommended for physician use by the American Academy of Pediatrics.

Ninety-six female adolescents participated in this study. Eighteen percent of them (n=17) had iron deficiency, and 5% (n=5) had iron-deficiency anemia.

Both the Bright Futures questions and the researchers’ risk assessment questionnaire poorly predicted ferritin and hemoglobin values in these subjects.

Mean differences in depression, poor attention, food insecurity, daytime sleepiness, and body mass index percentile were not significantly associated with ferritin or hemoglobin.

Conclusions

The results of these 2 studies suggest that risk factors and assessments cannot accurately determine which young women should receive testing for iron deficiency, although results from the first study might be used to determine when testing should occur.

“I think we need to establish the optimal timing for an objective assessment of adolescent iron deficiency and anemia,” Dr Sekhar said.

She believes the appropriate age may be 16 years old, when most females will have been menstruating for at least 3 years.

Further research will be needed to determine which blood test for iron deficiency without anemia is accurate, cost-efficient, and practical for routine doctor’s office use.

This test should be given with hemoglobin testing to catch all young women on the spectrum of iron deficiency, Dr Sekhar said.

Photo by Juan D. Alfonso

A pair of studies suggest physicians should consider testing female adolescents for iron deficiency within a few years of starting menses.

Women are typically tested for anemia in their teens, with a quick and affordable hemoglobin test.

However, iron deficiency can develop years before anemia and can be missed by hemoglobin testing alone.

Blood tests for iron deficiency without anemia are more costly and more difficult to obtain than hemoglobin testing for anemia.

Deepa Sekhar, MD, of Penn State College of Medicine in Hershey, Pennsylvania, and her colleagues set out to determine risk factors for iron deficiency without anemia in order to pinpoint which women could benefit most from the more costly testing.

The results of the researchers’ 2 studies were published in PLOS ONE and The Journal of Pediatrics.

PLOS ONE study

The researchers evaluated data from 6216 females, ages 12 to 49, who took part in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2010. As part of the survey, participants were tested for both iron deficiency and anemia.

Eight percent of all subjects (n=494) had iron deficiency.

Nine percent (n=250) of non-anemic younger women (ages 12-21) had iron deficiency, as did 7% (n=244) of older women (ages 22-49) who were not anemic.

The researchers looked at potential risk factors for iron deficiency, including the age when women started menstruating, as well as their race/ethnicity, poverty status, food insecurity, tobacco or nicotine use, dietary information, body mass index, and physical activity.

All of these factors have been associated with iron-deficiency anemia in women in prior studies.

In this study, there was only 1 risk factor significantly associated with iron deficiency without anemia.

Young women (ages 12-21) who had been menstruating for more than 3 years had a significantly higher risk of iron deficiency without anemia (risk ratio=3.18).

The Journal of Pediatrics study

In this study, the researchers looked at whether a questionnaire could better predict iron status.

The questionnaire included questions on depression, poor attention, and daytime sleepiness, all of which have been associated with iron deficiency or iron-deficiency anemia, but were not captured in the prior NHANES analyses.

This questionnaire was compared to the 4 questions assessing iron-deficiency anemia risk in the Bright Futures Adolescent Previsit Questionnaire, a survey recommended for physician use by the American Academy of Pediatrics.

Ninety-six female adolescents participated in this study. Eighteen percent of them (n=17) had iron deficiency, and 5% (n=5) had iron-deficiency anemia.

Both the Bright Futures questions and the researchers’ risk assessment questionnaire poorly predicted ferritin and hemoglobin values in these subjects.

Mean differences in depression, poor attention, food insecurity, daytime sleepiness, and body mass index percentile were not significantly associated with ferritin or hemoglobin.

Conclusions

The results of these 2 studies suggest that risk factors and assessments cannot accurately determine which young women should receive testing for iron deficiency, although results from the first study might be used to determine when testing should occur.

“I think we need to establish the optimal timing for an objective assessment of adolescent iron deficiency and anemia,” Dr Sekhar said.

She believes the appropriate age may be 16 years old, when most females will have been menstruating for at least 3 years.

Further research will be needed to determine which blood test for iron deficiency without anemia is accurate, cost-efficient, and practical for routine doctor’s office use.

This test should be given with hemoglobin testing to catch all young women on the spectrum of iron deficiency, Dr Sekhar said.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to DSP-7888, an investigational cancer peptide vaccine, for the treatment of myelodysplastic syndromes (MDS).

DSP-7888 contains peptides to induce Wilms’ tumor gene 1 (WT1)-specific cytotoxic T lymphocytes and helper T cells, which attack WT1-expressing cancerous cells found in various hematologic and solid tumor malignancies.

DSP-7888 is being developed by Boston Biomedical, Inc.

The first clinical data for DSP-7888, from a phase 1/2 study in patients with MDS who progressed on or after first-line azacitidine treatment, were presented at the 2016 ASH Annual Meeting.

Results were reported in 12 patients—7 with higher-risk MDS and 5 with lower-risk disease.

DSP-7888 was given at doses of 3.5 mg/body (n=6) or 10.5 mg/body (n=6) by intradermal injections every 2 to 4 weeks.

There were no dose-limiting toxicities. The most common adverse event was injection site reactions. Six patients had grade 3 injection site reactions.

There were 5 serious adverse events—3 injection site reactions, 1 case of pyrexia, and 1 case of myocarditis.

Eight patients had stable disease, 2 with hematological improvements.

Cytotoxic T lymphocyte induction was observed in 6 patients, and delayed type hypersensitivity response was observed in 10 patients.

About orphan designation

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

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

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to DSP-7888, an investigational cancer peptide vaccine, for the treatment of myelodysplastic syndromes (MDS).

DSP-7888 contains peptides to induce Wilms’ tumor gene 1 (WT1)-specific cytotoxic T lymphocytes and helper T cells, which attack WT1-expressing cancerous cells found in various hematologic and solid tumor malignancies.

DSP-7888 is being developed by Boston Biomedical, Inc.

The first clinical data for DSP-7888, from a phase 1/2 study in patients with MDS who progressed on or after first-line azacitidine treatment, were presented at the 2016 ASH Annual Meeting.

Results were reported in 12 patients—7 with higher-risk MDS and 5 with lower-risk disease.

DSP-7888 was given at doses of 3.5 mg/body (n=6) or 10.5 mg/body (n=6) by intradermal injections every 2 to 4 weeks.

There were no dose-limiting toxicities. The most common adverse event was injection site reactions. Six patients had grade 3 injection site reactions.

There were 5 serious adverse events—3 injection site reactions, 1 case of pyrexia, and 1 case of myocarditis.

Eight patients had stable disease, 2 with hematological improvements.

Cytotoxic T lymphocyte induction was observed in 6 patients, and delayed type hypersensitivity response was observed in 10 patients.

About orphan designation

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

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

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted orphan drug designation to DSP-7888, an investigational cancer peptide vaccine, for the treatment of myelodysplastic syndromes (MDS).

DSP-7888 contains peptides to induce Wilms’ tumor gene 1 (WT1)-specific cytotoxic T lymphocytes and helper T cells, which attack WT1-expressing cancerous cells found in various hematologic and solid tumor malignancies.

DSP-7888 is being developed by Boston Biomedical, Inc.

The first clinical data for DSP-7888, from a phase 1/2 study in patients with MDS who progressed on or after first-line azacitidine treatment, were presented at the 2016 ASH Annual Meeting.

Results were reported in 12 patients—7 with higher-risk MDS and 5 with lower-risk disease.

DSP-7888 was given at doses of 3.5 mg/body (n=6) or 10.5 mg/body (n=6) by intradermal injections every 2 to 4 weeks.

There were no dose-limiting toxicities. The most common adverse event was injection site reactions. Six patients had grade 3 injection site reactions.

There were 5 serious adverse events—3 injection site reactions, 1 case of pyrexia, and 1 case of myocarditis.

Eight patients had stable disease, 2 with hematological improvements.

Cytotoxic T lymphocyte induction was observed in 6 patients, and delayed type hypersensitivity response was observed in 10 patients.

About orphan designation

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

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

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted approval for L-glutamine oral powder (Endari), the first treatment approved to treat sickle cell disease (SCD) in the US in nearly 20 years.

L-glutamine oral powder, a product developed by Emmaus Medical Inc., is intended to reduce severe complications of SCD in patients age 5 and older.

The FDA’s approval of L-glutamine was supported by efficacy data from a phase 3 trial.

The trial enrolled 230 adults and children with SCD, and they were randomized to receive L-glutamine or placebo.

Patients who received L-glutamine had fewer sickle cell crises, hospitalizations, cumulative hospital days, and cases of acute chest syndrome than patients who received placebo.

Results from this trial were presented at the 2014 ASH Annual Meeting.

The FDA approval of L-glutamine was also supported by safety data from 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase 2 and phase 3 studies.

Based on these data, L-glutamine was considered well-tolerated in pediatric and adult patients. The most common adverse events (occurring in more than 10% of patients receiving L-glutamine) were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain (non-cardiac).

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted approval for L-glutamine oral powder (Endari), the first treatment approved to treat sickle cell disease (SCD) in the US in nearly 20 years.

L-glutamine oral powder, a product developed by Emmaus Medical Inc., is intended to reduce severe complications of SCD in patients age 5 and older.

The FDA’s approval of L-glutamine was supported by efficacy data from a phase 3 trial.

The trial enrolled 230 adults and children with SCD, and they were randomized to receive L-glutamine or placebo.

Patients who received L-glutamine had fewer sickle cell crises, hospitalizations, cumulative hospital days, and cases of acute chest syndrome than patients who received placebo.

Results from this trial were presented at the 2014 ASH Annual Meeting.

The FDA approval of L-glutamine was also supported by safety data from 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase 2 and phase 3 studies.

Based on these data, L-glutamine was considered well-tolerated in pediatric and adult patients. The most common adverse events (occurring in more than 10% of patients receiving L-glutamine) were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain (non-cardiac).

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted approval for L-glutamine oral powder (Endari), the first treatment approved to treat sickle cell disease (SCD) in the US in nearly 20 years.

L-glutamine oral powder, a product developed by Emmaus Medical Inc., is intended to reduce severe complications of SCD in patients age 5 and older.

The FDA’s approval of L-glutamine was supported by efficacy data from a phase 3 trial.

The trial enrolled 230 adults and children with SCD, and they were randomized to receive L-glutamine or placebo.

Patients who received L-glutamine had fewer sickle cell crises, hospitalizations, cumulative hospital days, and cases of acute chest syndrome than patients who received placebo.

Results from this trial were presented at the 2014 ASH Annual Meeting.

The FDA approval of L-glutamine was also supported by safety data from 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase 2 and phase 3 studies.

Based on these data, L-glutamine was considered well-tolerated in pediatric and adult patients. The most common adverse events (occurring in more than 10% of patients receiving L-glutamine) were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain (non-cardiac).

The Food and Drug Administration approved L-glutamine oral powder for reducing severe complications of sickle cell disease in patients aged 5 years and older.

The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.

The Food and Drug Administration approved L-glutamine oral powder for reducing severe complications of sickle cell disease in patients aged 5 years and older.

The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.

The Food and Drug Administration approved L-glutamine oral powder for reducing severe complications of sickle cell disease in patients aged 5 years and older.

The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.

Photo from UAB Hospital

MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.

Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.

Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).

“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.

He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.

The study was sponsored by Celgene in collaboration with Acceleron Pharma.

Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).

For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.

In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).

The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.

For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.

In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.

Efficacy in NTD patients

The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).

Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.

To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.

Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.

And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.

Efficacy in TD patients

The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).

Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.

Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.

Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.

Safety

The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).

Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).

Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.

Photo from UAB Hospital

MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.

Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.

Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).

“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.

He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.

The study was sponsored by Celgene in collaboration with Acceleron Pharma.

Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).

For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.

In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).

The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.

For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.

In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.

Efficacy in NTD patients

The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).

Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.

To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.

Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.

And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.

Efficacy in TD patients

The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).

Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.

Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.

Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.

Safety

The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).

Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).

Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.

Photo from UAB Hospital

MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.

Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.

Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).

“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.

He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.

The study was sponsored by Celgene in collaboration with Acceleron Pharma.

Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).

For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.

In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).

The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.

For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.

In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.

Efficacy in NTD patients

The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).

Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.

To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.

Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.

And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.

Efficacy in TD patients

The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).

Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.

Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.

Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.

Safety

The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).

Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).

Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Image by Betty Pace

The European Medicines Agency (EMA) has granted GBT440 access to the agency’s PRIority MEdicines (PRIME) program.

GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for sickle cell disease (SCD).

GBT440 works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

About PRIME

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Phase 1/2 trial

The GBT440 acceptance in the PRIME program was supported by data from an ongoing phase 1/2 trial (GBT440-001) in which researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of GBT440 in healthy subjects and adults with SCD.

Data from this trial were presented at the 2016 ASH Annual Meeting.

At that time, there were 41 SCD patients who had been receiving GBT440 for up to 6 months.

All of these patients experienced a “profound and durable” reduction in hemolysis, as assessed by hemoglobin, reticulocytes, and/or bilirubin, according to Global Blood Therapeutics.

Patients treated with GBT440 for at least 90 days demonstrated a “clinically significant” increase in hemoglobin (greater than 1 g/dL increase) when compared with placebo-treated patients (46% vs 0%; P=0.006).

Patients treated with GBT440 also had a sustained reduction in irreversibly sickled cells when compared with placebo-treated patients (-76.6% vs +9.7%; P<0.001).

The most common treatment-related adverse events were grade 1/2 headache and gastrointestinal disorders. These events occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events.

No sickle cell crises events occurred while participants were on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).

Image by Betty Pace

The European Medicines Agency (EMA) has granted GBT440 access to the agency’s PRIority MEdicines (PRIME) program.

GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for sickle cell disease (SCD).

GBT440 works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

About PRIME

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Phase 1/2 trial

The GBT440 acceptance in the PRIME program was supported by data from an ongoing phase 1/2 trial (GBT440-001) in which researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of GBT440 in healthy subjects and adults with SCD.

Data from this trial were presented at the 2016 ASH Annual Meeting.

At that time, there were 41 SCD patients who had been receiving GBT440 for up to 6 months.

All of these patients experienced a “profound and durable” reduction in hemolysis, as assessed by hemoglobin, reticulocytes, and/or bilirubin, according to Global Blood Therapeutics.

Patients treated with GBT440 for at least 90 days demonstrated a “clinically significant” increase in hemoglobin (greater than 1 g/dL increase) when compared with placebo-treated patients (46% vs 0%; P=0.006).

Patients treated with GBT440 also had a sustained reduction in irreversibly sickled cells when compared with placebo-treated patients (-76.6% vs +9.7%; P<0.001).

The most common treatment-related adverse events were grade 1/2 headache and gastrointestinal disorders. These events occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events.

No sickle cell crises events occurred while participants were on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).

Image by Betty Pace

The European Medicines Agency (EMA) has granted GBT440 access to the agency’s PRIority MEdicines (PRIME) program.

GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for sickle cell disease (SCD).

GBT440 works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

About PRIME

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Phase 1/2 trial

The GBT440 acceptance in the PRIME program was supported by data from an ongoing phase 1/2 trial (GBT440-001) in which researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of GBT440 in healthy subjects and adults with SCD.

Data from this trial were presented at the 2016 ASH Annual Meeting.

At that time, there were 41 SCD patients who had been receiving GBT440 for up to 6 months.

All of these patients experienced a “profound and durable” reduction in hemolysis, as assessed by hemoglobin, reticulocytes, and/or bilirubin, according to Global Blood Therapeutics.

Patients treated with GBT440 for at least 90 days demonstrated a “clinically significant” increase in hemoglobin (greater than 1 g/dL increase) when compared with placebo-treated patients (46% vs 0%; P=0.006).

Patients treated with GBT440 also had a sustained reduction in irreversibly sickled cells when compared with placebo-treated patients (-76.6% vs +9.7%; P<0.001).

The most common treatment-related adverse events were grade 1/2 headache and gastrointestinal disorders. These events occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events.

No sickle cell crises events occurred while participants were on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).

Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.

Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.

For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.

Main results showed that the patients with SCD had reduced levels of HDL₃ particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL₂ particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.

In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.

“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”

“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”

Study details

In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.

Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL₂ to HDL₃ that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.

Incubation of red blood cells with plasma from healthy individuals did not alter the HDL₂ to HDL₃ ratio, whereas incubation with plasma from patients with SCD increased this ratio.

When a fluorescent assay was used to assess oxidation, HDL₂ from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL₂ from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL₃.

Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL₂ from patients with SCD as compared with HDL₂ from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.

“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.

Dr. Soupene disclosed that he had no relevant conflicts of interest.

Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.

Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.

For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.

Main results showed that the patients with SCD had reduced levels of HDL₃ particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL₂ particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.

In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.

“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”

“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”

Study details

In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.

Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL₂ to HDL₃ that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.

Incubation of red blood cells with plasma from healthy individuals did not alter the HDL₂ to HDL₃ ratio, whereas incubation with plasma from patients with SCD increased this ratio.

When a fluorescent assay was used to assess oxidation, HDL₂ from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL₂ from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL₃.

Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL₂ from patients with SCD as compared with HDL₂ from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.

“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.

Dr. Soupene disclosed that he had no relevant conflicts of interest.

Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.

Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.

For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.

Main results showed that the patients with SCD had reduced levels of HDL₃ particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL₂ particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.

In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.

“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”

“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”

Study details

In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.

Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL₂ to HDL₃ that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.

Incubation of red blood cells with plasma from healthy individuals did not alter the HDL₂ to HDL₃ ratio, whereas incubation with plasma from patients with SCD increased this ratio.

When a fluorescent assay was used to assess oxidation, HDL₂ from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL₂ from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL₃.

Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL₂ from patients with SCD as compared with HDL₂ from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.

“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.

Dr. Soupene disclosed that he had no relevant conflicts of interest.

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”