Anemia

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan drug designation for BI 836858, an anti-CD33 monoclonal antibody (mAb), in the treatment of myelodysplastic syndromes (MDS).

BI 836858 previously received orphan designation for the treatment of acute myeloid leukemia (AML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases.

This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

About BI 836858

BI 836858 is a fully human, immunoglobulin G1 anti-CD33 mAb. It has been engineered for improved binding to FcgRIIIa to mediate natural killer cell antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells.

BI 836858 is being developed by Boehringer Ingelheim.

A phase 1/2 trial (NCT02240706) of BI 836858 in patients with MDS is ongoing. The phase 1 portion was designed to evaluate various doses of the mAb in patients with low or intermediate-1 risk MDS with symptomatic anemia.

The phase 2 portion was designed to compare BI 836858 plus best supportive care to best supportive care alone in patients with low- or intermediate-1-risk MDS who have symptomatic anemia but do not have a 5q deletion.

BI 836858 is also being tested in combination with decitabine in a phase 1/2 study (NCT02632721) of patients with AML.

The goals of the phase 1 portion and the phase 1 extension are to determine the maximum-tolerated dose/recommended dose, safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine.

The goals of the phase 2 portion of the study are to investigate the efficacy, safety, and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

BI 836858 was previously evaluated in combination with decitabine in a preclinical study. The combination exhibited activity against AML in vitro. The research was published in Blood last year.

BI 836858 is also being evaluated as part of the Leukemia & Lymphoma Society’s Beat AML Master Trial program to advance treatment for patients with AML.

In this trial, investigators are using genomic technology to identify AML mutations in newly diagnosed patients over the age of 60 and match the patients with an investigational drug or drugs best suited to attack the mutations found.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan drug designation for BI 836858, an anti-CD33 monoclonal antibody (mAb), in the treatment of myelodysplastic syndromes (MDS).

BI 836858 previously received orphan designation for the treatment of acute myeloid leukemia (AML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases.

This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

About BI 836858

BI 836858 is a fully human, immunoglobulin G1 anti-CD33 mAb. It has been engineered for improved binding to FcgRIIIa to mediate natural killer cell antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells.

BI 836858 is being developed by Boehringer Ingelheim.

A phase 1/2 trial (NCT02240706) of BI 836858 in patients with MDS is ongoing. The phase 1 portion was designed to evaluate various doses of the mAb in patients with low or intermediate-1 risk MDS with symptomatic anemia.

The phase 2 portion was designed to compare BI 836858 plus best supportive care to best supportive care alone in patients with low- or intermediate-1-risk MDS who have symptomatic anemia but do not have a 5q deletion.

BI 836858 is also being tested in combination with decitabine in a phase 1/2 study (NCT02632721) of patients with AML.

The goals of the phase 1 portion and the phase 1 extension are to determine the maximum-tolerated dose/recommended dose, safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine.

The goals of the phase 2 portion of the study are to investigate the efficacy, safety, and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

BI 836858 was previously evaluated in combination with decitabine in a preclinical study. The combination exhibited activity against AML in vitro. The research was published in Blood last year.

BI 836858 is also being evaluated as part of the Leukemia & Lymphoma Society’s Beat AML Master Trial program to advance treatment for patients with AML.

In this trial, investigators are using genomic technology to identify AML mutations in newly diagnosed patients over the age of 60 and match the patients with an investigational drug or drugs best suited to attack the mutations found.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan drug designation for BI 836858, an anti-CD33 monoclonal antibody (mAb), in the treatment of myelodysplastic syndromes (MDS).

BI 836858 previously received orphan designation for the treatment of acute myeloid leukemia (AML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases.

This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

About BI 836858

BI 836858 is a fully human, immunoglobulin G1 anti-CD33 mAb. It has been engineered for improved binding to FcgRIIIa to mediate natural killer cell antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells.

BI 836858 is being developed by Boehringer Ingelheim.

A phase 1/2 trial (NCT02240706) of BI 836858 in patients with MDS is ongoing. The phase 1 portion was designed to evaluate various doses of the mAb in patients with low or intermediate-1 risk MDS with symptomatic anemia.

The phase 2 portion was designed to compare BI 836858 plus best supportive care to best supportive care alone in patients with low- or intermediate-1-risk MDS who have symptomatic anemia but do not have a 5q deletion.

BI 836858 is also being tested in combination with decitabine in a phase 1/2 study (NCT02632721) of patients with AML.

The goals of the phase 1 portion and the phase 1 extension are to determine the maximum-tolerated dose/recommended dose, safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine.

The goals of the phase 2 portion of the study are to investigate the efficacy, safety, and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

BI 836858 was previously evaluated in combination with decitabine in a preclinical study. The combination exhibited activity against AML in vitro. The research was published in Blood last year.

BI 836858 is also being evaluated as part of the Leukemia & Lymphoma Society’s Beat AML Master Trial program to advance treatment for patients with AML.

In this trial, investigators are using genomic technology to identify AML mutations in newly diagnosed patients over the age of 60 and match the patients with an investigational drug or drugs best suited to attack the mutations found.

Image by Betty Pace

Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.

The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).

A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.

Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbA^T87Q), and there were no adverse events thought to be related to LentiGlobin BB305.

These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.

Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.

The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.

The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.

The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×10⁸ and 5.4×10⁸ total nucleated cells/kg harvested).

CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.

The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.

After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×10⁶ CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.

Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbA^T87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.

HbA^T87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.

Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.

No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).

During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.

The patient resumed regular school attendance and reported full participation in normal physical activities.

“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.

“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”

Image by Betty Pace

Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.

The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).

A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.

Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbA^T87Q), and there were no adverse events thought to be related to LentiGlobin BB305.

These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.

Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.

The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.

The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.

The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×10⁸ and 5.4×10⁸ total nucleated cells/kg harvested).

CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.

The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.

After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×10⁶ CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.

Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbA^T87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.

HbA^T87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.

Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.

No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).

During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.

The patient resumed regular school attendance and reported full participation in normal physical activities.

“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.

“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”

Image by Betty Pace

Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.

The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).

A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.

Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbA^T87Q), and there were no adverse events thought to be related to LentiGlobin BB305.

These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.

Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.

The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.

The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.

The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×10⁸ and 5.4×10⁸ total nucleated cells/kg harvested).

CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.

The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.

After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×10⁶ CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.

Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbA^T87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.

HbA^T87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.

Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.

No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).

During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.

The patient resumed regular school attendance and reported full participation in normal physical activities.

“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.

“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”

A teenage boy with sickle cell disease has been successfully treated with a therapy that uses a viral vector to insert functional genes into blood-producing stem cells.

The patient’s positive response to the intervention was first reported in 2015, and his clinical remission was reported in late 2016 at the American Society of Hematology’s annual meeting.

The new report, published online March 1 in the New England Journal of Medicine, contains the first detailed description of the case (2017;376:848-55).

Dr_Microbe/Thinkstock

A teenage boy with sickle cell disease has been successfully treated with a therapy that uses a viral vector to insert functional genes into blood-producing stem cells.

The patient’s positive response to the intervention was first reported in 2015, and his clinical remission was reported in late 2016 at the American Society of Hematology’s annual meeting.

The new report, published online March 1 in the New England Journal of Medicine, contains the first detailed description of the case (2017;376:848-55).

Dr_Microbe/Thinkstock

A teenage boy with sickle cell disease has been successfully treated with a therapy that uses a viral vector to insert functional genes into blood-producing stem cells.

The patient’s positive response to the intervention was first reported in 2015, and his clinical remission was reported in late 2016 at the American Society of Hematology’s annual meeting.

The new report, published online March 1 in the New England Journal of Medicine, contains the first detailed description of the case (2017;376:848-55).

Dr_Microbe/Thinkstock

Patients with beta thalassemia major who were chelated only with oral deferasirox experienced significant improvements in liver stiffness, both from baseline and compared with patients who interrupted deferasirox therapy because of pregnancy, according to a small prospective 5-year study.

Transient elastography showed that continuous therapy with deferasirox (median dose, 35 mg per kg) yielded an 0.85 kPa average improvement in liver stiffness compared with baseline (P = .02), reported Nikolaos Sousos of Aristotle University of Thessaloniki, Greece, and his associates (Br J Haematol. 2017 Jan 20. doi: 10.1111/bjh.14509).

In contrast, interrupting therapy for a median of 16 months because of successful pregnancy led to an average increase in liver stiffness of 1.84 kPa – a significant difference between groups (P = .005) even after the researchers controlled for gender, age, ferritin levels, and T2-weighted magnetic resonance imaging (MRI) measurements of iron deposition in the liver and heart.

Patients with beta thalassemia major often develop liver fibrosis because of excessive intestinal iron absorption, iron overload from transfusions, or hepatitis C virus infection, the investigators noted. The median age of the patients in this study was 32 years (range, 20-47 years), they were HCV negative, and they received regular transfusions to maintain hemoglobin levels above 95 g/L. The seven female participants who temporarily stopped deferasirox because of pregnancy all restarted therapy at least 8 months before their follow-up transient elastography liver stiffness measurement, the investigators reported.

T2-weighted MRI measurements of liver iron concentration also had improved at follow-up, reflecting “better control of iron overload,” although the difference from baseline was not statistically significant, the investigators noted. This result reinforces previous findings (Gastroenterology. 2011;141[4]:1202-11) that long-term deferasirox therapy can significantly improve liver fibrosis in patients with beta thalassemia, regardless of liver iron concentration, the researchers added. Together, those findings suggest that “improvement in liver fibrosis, rather than liver iron concentration should be the primary effect of chelation therapy,” they suggested.

The Research Committee of Aristotle University of Thessaloniki, Novartis Hellas (Novartis AG, Basel, Switzerland), and the Greek Thalassaemia Association funded the study. The authors declared having no competing interests.

Patients with beta thalassemia major who were chelated only with oral deferasirox experienced significant improvements in liver stiffness, both from baseline and compared with patients who interrupted deferasirox therapy because of pregnancy, according to a small prospective 5-year study.

Transient elastography showed that continuous therapy with deferasirox (median dose, 35 mg per kg) yielded an 0.85 kPa average improvement in liver stiffness compared with baseline (P = .02), reported Nikolaos Sousos of Aristotle University of Thessaloniki, Greece, and his associates (Br J Haematol. 2017 Jan 20. doi: 10.1111/bjh.14509).

In contrast, interrupting therapy for a median of 16 months because of successful pregnancy led to an average increase in liver stiffness of 1.84 kPa – a significant difference between groups (P = .005) even after the researchers controlled for gender, age, ferritin levels, and T2-weighted magnetic resonance imaging (MRI) measurements of iron deposition in the liver and heart.

Patients with beta thalassemia major often develop liver fibrosis because of excessive intestinal iron absorption, iron overload from transfusions, or hepatitis C virus infection, the investigators noted. The median age of the patients in this study was 32 years (range, 20-47 years), they were HCV negative, and they received regular transfusions to maintain hemoglobin levels above 95 g/L. The seven female participants who temporarily stopped deferasirox because of pregnancy all restarted therapy at least 8 months before their follow-up transient elastography liver stiffness measurement, the investigators reported.

T2-weighted MRI measurements of liver iron concentration also had improved at follow-up, reflecting “better control of iron overload,” although the difference from baseline was not statistically significant, the investigators noted. This result reinforces previous findings (Gastroenterology. 2011;141[4]:1202-11) that long-term deferasirox therapy can significantly improve liver fibrosis in patients with beta thalassemia, regardless of liver iron concentration, the researchers added. Together, those findings suggest that “improvement in liver fibrosis, rather than liver iron concentration should be the primary effect of chelation therapy,” they suggested.

The Research Committee of Aristotle University of Thessaloniki, Novartis Hellas (Novartis AG, Basel, Switzerland), and the Greek Thalassaemia Association funded the study. The authors declared having no competing interests.

Patients with beta thalassemia major who were chelated only with oral deferasirox experienced significant improvements in liver stiffness, both from baseline and compared with patients who interrupted deferasirox therapy because of pregnancy, according to a small prospective 5-year study.

Transient elastography showed that continuous therapy with deferasirox (median dose, 35 mg per kg) yielded an 0.85 kPa average improvement in liver stiffness compared with baseline (P = .02), reported Nikolaos Sousos of Aristotle University of Thessaloniki, Greece, and his associates (Br J Haematol. 2017 Jan 20. doi: 10.1111/bjh.14509).

In contrast, interrupting therapy for a median of 16 months because of successful pregnancy led to an average increase in liver stiffness of 1.84 kPa – a significant difference between groups (P = .005) even after the researchers controlled for gender, age, ferritin levels, and T2-weighted magnetic resonance imaging (MRI) measurements of iron deposition in the liver and heart.

Patients with beta thalassemia major often develop liver fibrosis because of excessive intestinal iron absorption, iron overload from transfusions, or hepatitis C virus infection, the investigators noted. The median age of the patients in this study was 32 years (range, 20-47 years), they were HCV negative, and they received regular transfusions to maintain hemoglobin levels above 95 g/L. The seven female participants who temporarily stopped deferasirox because of pregnancy all restarted therapy at least 8 months before their follow-up transient elastography liver stiffness measurement, the investigators reported.

T2-weighted MRI measurements of liver iron concentration also had improved at follow-up, reflecting “better control of iron overload,” although the difference from baseline was not statistically significant, the investigators noted. This result reinforces previous findings (Gastroenterology. 2011;141[4]:1202-11) that long-term deferasirox therapy can significantly improve liver fibrosis in patients with beta thalassemia, regardless of liver iron concentration, the researchers added. Together, those findings suggest that “improvement in liver fibrosis, rather than liver iron concentration should be the primary effect of chelation therapy,” they suggested.

The Research Committee of Aristotle University of Thessaloniki, Novartis Hellas (Novartis AG, Basel, Switzerland), and the Greek Thalassaemia Association funded the study. The authors declared having no competing interests.

Among adults with sickle cell disease, early mortality is associated with increasing tricuspid regurgitant jet velocity on ECG, reticulocyte count, brain natriuretic peptide levels, and patient age, and with decreasing fetal hemoglobin levels, according to a report published in Haematologica.

Although survival improved among children with sickle cell disease (SCD) following the Food and Drug Administration approval of hydroxyurea treatment in 1998, mortality remains high among adult patients. To examine the clinical and laboratory factors underlying early mortality in this patient population, researchers combined the findings from their single-center cohort study of 161 clinic patients and a meta-analysis of nine studies in the literature, for a total of 3,257 participants. This is “the largest number of SCD patients in whom risk factors for mortality have been evaluated in the hydroxyurea era,” said Poulami Maitra, PhD, of the department of biostatistics at the University of North Carolina, Chapel Hill, and her associates.

The clinic cohort had a median age of 36 years (range, 18-71 years), and there were 29 deaths during a median follow-up of 7.2 years. The median age at death was 48 years. Similarly, the median age at death ranged from 39.7 to 53 years in the meta-analysis.

In the combined cohort, patients who had a tricuspid regurgitant jet velocity of 2.5 m/s or more had three times greater risk of dying than did patients who had lower values, and the risk of dying was approximately doubled for every 1-U elevation in log(N-terminal pro-B type natriuretic peptide), which reflects increasing ventricular strain. Both links have been reported before. The findings confirm that recent clinical practice guidelines recommending periodic echocardiographic screening for these patients is warranted, the investigators said (Haematologica. 2017 Jan 19. doi: 10.3324/haematol.2016.153791).

The hazard of dying was 5% higher for every 1% increase in reticulocyte count, which suggests that hemolysis contributes to early mortality in these patients. The hazard of dying also was 3% lower for every 1% increase in fetal hemoglobin. This association with fetal hemoglobin is the basis for the development of drugs that raise that level, such as hydroxyurea.

Mortality was 30% higher for every 10-year increase in patient age, reflecting the fact that people with SCD show increasing end-organ damage over time that contributes to their mortality, Dr. Maitra and her associates said.

This work was supported by the National Institutes of Health and the North Carolina Sickle Cell Program. Dr. Maitra reported having no relevant financial disclosures; one of her associates reported serving as a consultant to Pfizer and Global Blood Therapeutics.

Among adults with sickle cell disease, early mortality is associated with increasing tricuspid regurgitant jet velocity on ECG, reticulocyte count, brain natriuretic peptide levels, and patient age, and with decreasing fetal hemoglobin levels, according to a report published in Haematologica.

Although survival improved among children with sickle cell disease (SCD) following the Food and Drug Administration approval of hydroxyurea treatment in 1998, mortality remains high among adult patients. To examine the clinical and laboratory factors underlying early mortality in this patient population, researchers combined the findings from their single-center cohort study of 161 clinic patients and a meta-analysis of nine studies in the literature, for a total of 3,257 participants. This is “the largest number of SCD patients in whom risk factors for mortality have been evaluated in the hydroxyurea era,” said Poulami Maitra, PhD, of the department of biostatistics at the University of North Carolina, Chapel Hill, and her associates.

The clinic cohort had a median age of 36 years (range, 18-71 years), and there were 29 deaths during a median follow-up of 7.2 years. The median age at death was 48 years. Similarly, the median age at death ranged from 39.7 to 53 years in the meta-analysis.

In the combined cohort, patients who had a tricuspid regurgitant jet velocity of 2.5 m/s or more had three times greater risk of dying than did patients who had lower values, and the risk of dying was approximately doubled for every 1-U elevation in log(N-terminal pro-B type natriuretic peptide), which reflects increasing ventricular strain. Both links have been reported before. The findings confirm that recent clinical practice guidelines recommending periodic echocardiographic screening for these patients is warranted, the investigators said (Haematologica. 2017 Jan 19. doi: 10.3324/haematol.2016.153791).

The hazard of dying was 5% higher for every 1% increase in reticulocyte count, which suggests that hemolysis contributes to early mortality in these patients. The hazard of dying also was 3% lower for every 1% increase in fetal hemoglobin. This association with fetal hemoglobin is the basis for the development of drugs that raise that level, such as hydroxyurea.

Mortality was 30% higher for every 10-year increase in patient age, reflecting the fact that people with SCD show increasing end-organ damage over time that contributes to their mortality, Dr. Maitra and her associates said.

This work was supported by the National Institutes of Health and the North Carolina Sickle Cell Program. Dr. Maitra reported having no relevant financial disclosures; one of her associates reported serving as a consultant to Pfizer and Global Blood Therapeutics.

Among adults with sickle cell disease, early mortality is associated with increasing tricuspid regurgitant jet velocity on ECG, reticulocyte count, brain natriuretic peptide levels, and patient age, and with decreasing fetal hemoglobin levels, according to a report published in Haematologica.

Although survival improved among children with sickle cell disease (SCD) following the Food and Drug Administration approval of hydroxyurea treatment in 1998, mortality remains high among adult patients. To examine the clinical and laboratory factors underlying early mortality in this patient population, researchers combined the findings from their single-center cohort study of 161 clinic patients and a meta-analysis of nine studies in the literature, for a total of 3,257 participants. This is “the largest number of SCD patients in whom risk factors for mortality have been evaluated in the hydroxyurea era,” said Poulami Maitra, PhD, of the department of biostatistics at the University of North Carolina, Chapel Hill, and her associates.

The clinic cohort had a median age of 36 years (range, 18-71 years), and there were 29 deaths during a median follow-up of 7.2 years. The median age at death was 48 years. Similarly, the median age at death ranged from 39.7 to 53 years in the meta-analysis.

In the combined cohort, patients who had a tricuspid regurgitant jet velocity of 2.5 m/s or more had three times greater risk of dying than did patients who had lower values, and the risk of dying was approximately doubled for every 1-U elevation in log(N-terminal pro-B type natriuretic peptide), which reflects increasing ventricular strain. Both links have been reported before. The findings confirm that recent clinical practice guidelines recommending periodic echocardiographic screening for these patients is warranted, the investigators said (Haematologica. 2017 Jan 19. doi: 10.3324/haematol.2016.153791).

The hazard of dying was 5% higher for every 1% increase in reticulocyte count, which suggests that hemolysis contributes to early mortality in these patients. The hazard of dying also was 3% lower for every 1% increase in fetal hemoglobin. This association with fetal hemoglobin is the basis for the development of drugs that raise that level, such as hydroxyurea.

Mortality was 30% higher for every 10-year increase in patient age, reflecting the fact that people with SCD show increasing end-organ damage over time that contributes to their mortality, Dr. Maitra and her associates said.

This work was supported by the National Institutes of Health and the North Carolina Sickle Cell Program. Dr. Maitra reported having no relevant financial disclosures; one of her associates reported serving as a consultant to Pfizer and Global Blood Therapeutics.

Extended-release oxymorphone hydrochloride (Opana ER) tablets contain an inert ingredient that can trigger acute microangiopathic hemolytic anemia and thrombocytopenia in those who abuse the drug via intravenous injection, Ryan Hunt, of the Food and Drug Administration, and his colleagues reported.

High-molecular-weight polyethylene oxide appeared to be the cause of acute cases of thrombotic microangiopathy in three patients who were treated in the emergency department of a single hospital in Tennessee. All had chest pain, dyspnea, visual impairment, microangiopathic hemolytic anemia and thrombocytopenia, increased lactate dehydrogenase, and undetectable haptoglobin serum levels. Two patients also had acute renal failure. Plasma exchange therapy was initiated in all three; one required additional hemodialysis.

ADAMTS13 activity was normal in blood samples obtained in two patients before they started plasma exchange. Histologic evidence of thrombotic microangiopathy with endothelial swelling of arterioles and acute tubular injury without deposition of immune complexes was seen in kidney biopsies performed in two patients. In addition, gelatinous material occluded the dialysis catheter and apheresis tubings during the initial plasma exchange sessions, the researchers reported (Blood. 2017;129[7]:896-905).

To test the association of polyethylene oxide with thrombotic microangiopathy, the researchers heated a 40-mg Opana ER tablet cut in several pieces in a spoon with 2 mL water until boiling. They injected guinea pigs with 0.1 or 0.3 mg/kg of the extracted polyethylene oxide, either as a single dose or as five doses given at 1.5-hour intervals. A dose-dependent increase of polyethylene oxide in plasma peaked at 8 hours after the first dose was measured and paralleled with intravascular hemolysis with increased plasma concentration of free hemoglobin, schistocytes in the peripheral blood smear, and thrombocytopenia. Spiking control blood samples in vitro with polyethylene oxide did not result in hemolysis.

“Although injection abuse of prescription opioids is highly concentrated in certain regions of the United States, particularly in rural Appalachia, all physicians should be highly inquisitive of IV drug abuse when presented with cases of [thrombotic microangiopathy],” the researchers concluded.

The researchers had no relevant conflicts of interest. One of the researchers is employed by Quest Diagnostics.

[email protected]

On Twitter @maryjodales

Extended-release oxymorphone hydrochloride (Opana ER) tablets contain an inert ingredient that can trigger acute microangiopathic hemolytic anemia and thrombocytopenia in those who abuse the drug via intravenous injection, Ryan Hunt, of the Food and Drug Administration, and his colleagues reported.

High-molecular-weight polyethylene oxide appeared to be the cause of acute cases of thrombotic microangiopathy in three patients who were treated in the emergency department of a single hospital in Tennessee. All had chest pain, dyspnea, visual impairment, microangiopathic hemolytic anemia and thrombocytopenia, increased lactate dehydrogenase, and undetectable haptoglobin serum levels. Two patients also had acute renal failure. Plasma exchange therapy was initiated in all three; one required additional hemodialysis.

ADAMTS13 activity was normal in blood samples obtained in two patients before they started plasma exchange. Histologic evidence of thrombotic microangiopathy with endothelial swelling of arterioles and acute tubular injury without deposition of immune complexes was seen in kidney biopsies performed in two patients. In addition, gelatinous material occluded the dialysis catheter and apheresis tubings during the initial plasma exchange sessions, the researchers reported (Blood. 2017;129[7]:896-905).

To test the association of polyethylene oxide with thrombotic microangiopathy, the researchers heated a 40-mg Opana ER tablet cut in several pieces in a spoon with 2 mL water until boiling. They injected guinea pigs with 0.1 or 0.3 mg/kg of the extracted polyethylene oxide, either as a single dose or as five doses given at 1.5-hour intervals. A dose-dependent increase of polyethylene oxide in plasma peaked at 8 hours after the first dose was measured and paralleled with intravascular hemolysis with increased plasma concentration of free hemoglobin, schistocytes in the peripheral blood smear, and thrombocytopenia. Spiking control blood samples in vitro with polyethylene oxide did not result in hemolysis.

“Although injection abuse of prescription opioids is highly concentrated in certain regions of the United States, particularly in rural Appalachia, all physicians should be highly inquisitive of IV drug abuse when presented with cases of [thrombotic microangiopathy],” the researchers concluded.

The researchers had no relevant conflicts of interest. One of the researchers is employed by Quest Diagnostics.

[email protected]

On Twitter @maryjodales

Extended-release oxymorphone hydrochloride (Opana ER) tablets contain an inert ingredient that can trigger acute microangiopathic hemolytic anemia and thrombocytopenia in those who abuse the drug via intravenous injection, Ryan Hunt, of the Food and Drug Administration, and his colleagues reported.

High-molecular-weight polyethylene oxide appeared to be the cause of acute cases of thrombotic microangiopathy in three patients who were treated in the emergency department of a single hospital in Tennessee. All had chest pain, dyspnea, visual impairment, microangiopathic hemolytic anemia and thrombocytopenia, increased lactate dehydrogenase, and undetectable haptoglobin serum levels. Two patients also had acute renal failure. Plasma exchange therapy was initiated in all three; one required additional hemodialysis.

ADAMTS13 activity was normal in blood samples obtained in two patients before they started plasma exchange. Histologic evidence of thrombotic microangiopathy with endothelial swelling of arterioles and acute tubular injury without deposition of immune complexes was seen in kidney biopsies performed in two patients. In addition, gelatinous material occluded the dialysis catheter and apheresis tubings during the initial plasma exchange sessions, the researchers reported (Blood. 2017;129[7]:896-905).

To test the association of polyethylene oxide with thrombotic microangiopathy, the researchers heated a 40-mg Opana ER tablet cut in several pieces in a spoon with 2 mL water until boiling. They injected guinea pigs with 0.1 or 0.3 mg/kg of the extracted polyethylene oxide, either as a single dose or as five doses given at 1.5-hour intervals. A dose-dependent increase of polyethylene oxide in plasma peaked at 8 hours after the first dose was measured and paralleled with intravascular hemolysis with increased plasma concentration of free hemoglobin, schistocytes in the peripheral blood smear, and thrombocytopenia. Spiking control blood samples in vitro with polyethylene oxide did not result in hemolysis.

“Although injection abuse of prescription opioids is highly concentrated in certain regions of the United States, particularly in rural Appalachia, all physicians should be highly inquisitive of IV drug abuse when presented with cases of [thrombotic microangiopathy],” the researchers concluded.

The researchers had no relevant conflicts of interest. One of the researchers is employed by Quest Diagnostics.

[email protected]

On Twitter @maryjodales

Testosterone treatment may have beneficial effects on unexplained anemia or bone density in men with age-related low testosterone, but at the cost of an increase in coronary artery plaque and with no benefit on cognitive function, new research suggests.

The results of four of the seven Testosterone Trials were published Feb. 21 in JAMA and JAMA Internal Medicine, adding to a growing body of research on the impact of testosterone supplementation but without finding clear evidence of an overall benefit.

In the double-blind, multicenter Anemia Trial, 788 men aged 65 years or older with average testosterone levels of less than 275 ng/dL were allocated to 12 months of testosterone gel or placebo. The group included 126 individuals with a hemoglobin level at or below 12.7 g/dL (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9540).

The study found that significantly more men who received testosterone treatment experienced increases in hemoglobin concentration of 1 g/dL or more above baseline, compared with those who received the placebo gel (54% vs. 15%; 95% CI 3.7-277.8; P = .002).

This effect was seen in men with known causes of anemia, such as myelodysplasia, iron deficiency, B₁₂ deficiency, or chronic inflammation or disease; in men with anemia of unknown case; and in men who weren’t anemic.

After 12 months, more than half of the testosterone-treated men who started the study with unexplained anemia were no longer anemic, compared with around one-quarter of the placebo-treated men (58.3% vs. 22.2%). The men treated with placebo also had lower average hemoglobin level changes, compared with those treated with testosterone.

“Increases in hemoglobin levels were positively and significantly associated with participants’ global impression of change in overall health and energy,” wrote Cindy N. Roy, PhD, of Johns Hopkins University, Baltimore, and her coauthors.

Bone mineral density

A second trial examined the effect of 12 months of testosterone gel or placebo on bone mineral density in a group of 211 men with average testosterone concentrations less than 275 ng/L (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9539). The treatment increased median serum concentrations of total testosterone, free testosterone, and estradiol to within the normal ranges for young men.

The study showed significantly greater increases – measured by quantitative computed tomography – with testosterone treatment, compared with placebo, in spine trabecular, spine peripheral, hip trabecular, and peripheral volumetric bone mineral density, as well as in mean estimated strength of spine trabecular bone, spine peripheral bone, and hip trabecular and peripheral bone.

For the primary outcome of mean lumbar spine trabecular volumetric bone mineral density, testosterone treatment was associated with a mean increase of 7.5%, compared with a 0.8% increase with placebo.

Researchers also noted that the magnitude of the increase in spine trabecular bone mineral density from baseline was significantly associated with changes in total testosterone and estradiol.

However, there were no significant differences in fracture rate, with six fractures reported in each group during the year of treatment. In the observation year after treatment, three fractures were reported in the testosterone arm and four in the placebo arm.

“These results are unequivocal compared with prior studies of the effect of testosterone treatment on bone in older men, in spite of treatment limited to 1 year, perhaps because the mean pretreatment testosterone level was lower and the sample size larger than in prior studies, and because the primary outcome in this trial was vBMD by QCT,” wrote Peter J. Snyder, MD, of the University of Pennsylvania, Philadelphia, and his coauthors.

Coronary artery plaque

However, a third trial – this one in 170 men with low testosterone and symptoms suggestive of hypogonadism – found significantly greater increases in noncalcified plaque volume, median total plaque volume, and median coronary artery calcification score among the 88 men assigned to 12 months of testosterone gel, compared with those assigned to placebo.

The men treated with testosterone showed a mean increase in noncalcified coronary artery plaque volume of 40 mm³, compared with 4 mm³ in men given the placebo gel, and a mean increase in total plaque volume of 57 mm³ with testosterone and 21 mm³ with placebo (JAMA. 2017 Feb 21;317[7]:708-16).

There were no significant differences between the groups in change to coronary artery calcium score, and there were no adverse cardiovascular events reported in either group, despite the fact that around half the participants had severe atherosclerosis at baseline.

“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning, because any limitation of the vascular lumen could be considered deleterious,” wrote Matthew J. Budoff, MD, of the Los Angeles Biomedical Research Institute, Torrance, Calif., and his coauthors. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”

However, the investigators pointed out that the trial was neither large enough nor long enough to draw conclusions about the cardiovascular risks of testosterone treatment, and they called for larger studies to explore the association.

Cognitive function

The fourth study looked at mean change in cognitive function from baseline in 493 men with a serum testosterone level less than 275 ng/dL, impaired sexual function, physical function, or vitality, and who met the criteria for age-associated memory impairment. Half the participants were assigned to 12 months of testosterone gel, and half were assigned to placebo gel (JAMA. 2017 Feb 21;317[7]:717-27).

Researchers found no significant differences between the two groups from baseline to 6 months and 12 months in mean change in delayed paragraph recall score, visual memory, executive function, or spatial ability.

“The lack of association between testosterone treatment and cognition was apparent across all cognitive domains assessed among men with [age-associated memory impairment], in spite of an increase in circulating total and free testosterone concentrations in the testosterone group to levels typical of men aged 19-40 years,” wrote Susan M. Resnick, PhD, of the National Institute on Aging, and her coauthors.

The Testosterone Trials were supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Diseases and Stroke, the National Institute of Child Health and Human Development, and AbbVie, which also provided the AndroGel, and placebo gel. Authors from the trials declared a range of funding, consultancies, and other support from the pharmaceutical industry, including AbbVie. One author declared a pending patent for a free testosterone calculator.

Testosterone treatment may have beneficial effects on unexplained anemia or bone density in men with age-related low testosterone, but at the cost of an increase in coronary artery plaque and with no benefit on cognitive function, new research suggests.

The results of four of the seven Testosterone Trials were published Feb. 21 in JAMA and JAMA Internal Medicine, adding to a growing body of research on the impact of testosterone supplementation but without finding clear evidence of an overall benefit.

In the double-blind, multicenter Anemia Trial, 788 men aged 65 years or older with average testosterone levels of less than 275 ng/dL were allocated to 12 months of testosterone gel or placebo. The group included 126 individuals with a hemoglobin level at or below 12.7 g/dL (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9540).

The study found that significantly more men who received testosterone treatment experienced increases in hemoglobin concentration of 1 g/dL or more above baseline, compared with those who received the placebo gel (54% vs. 15%; 95% CI 3.7-277.8; P = .002).

This effect was seen in men with known causes of anemia, such as myelodysplasia, iron deficiency, B₁₂ deficiency, or chronic inflammation or disease; in men with anemia of unknown case; and in men who weren’t anemic.

After 12 months, more than half of the testosterone-treated men who started the study with unexplained anemia were no longer anemic, compared with around one-quarter of the placebo-treated men (58.3% vs. 22.2%). The men treated with placebo also had lower average hemoglobin level changes, compared with those treated with testosterone.

“Increases in hemoglobin levels were positively and significantly associated with participants’ global impression of change in overall health and energy,” wrote Cindy N. Roy, PhD, of Johns Hopkins University, Baltimore, and her coauthors.

Bone mineral density

A second trial examined the effect of 12 months of testosterone gel or placebo on bone mineral density in a group of 211 men with average testosterone concentrations less than 275 ng/L (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9539). The treatment increased median serum concentrations of total testosterone, free testosterone, and estradiol to within the normal ranges for young men.

The study showed significantly greater increases – measured by quantitative computed tomography – with testosterone treatment, compared with placebo, in spine trabecular, spine peripheral, hip trabecular, and peripheral volumetric bone mineral density, as well as in mean estimated strength of spine trabecular bone, spine peripheral bone, and hip trabecular and peripheral bone.

For the primary outcome of mean lumbar spine trabecular volumetric bone mineral density, testosterone treatment was associated with a mean increase of 7.5%, compared with a 0.8% increase with placebo.

Researchers also noted that the magnitude of the increase in spine trabecular bone mineral density from baseline was significantly associated with changes in total testosterone and estradiol.

However, there were no significant differences in fracture rate, with six fractures reported in each group during the year of treatment. In the observation year after treatment, three fractures were reported in the testosterone arm and four in the placebo arm.

“These results are unequivocal compared with prior studies of the effect of testosterone treatment on bone in older men, in spite of treatment limited to 1 year, perhaps because the mean pretreatment testosterone level was lower and the sample size larger than in prior studies, and because the primary outcome in this trial was vBMD by QCT,” wrote Peter J. Snyder, MD, of the University of Pennsylvania, Philadelphia, and his coauthors.

Coronary artery plaque

However, a third trial – this one in 170 men with low testosterone and symptoms suggestive of hypogonadism – found significantly greater increases in noncalcified plaque volume, median total plaque volume, and median coronary artery calcification score among the 88 men assigned to 12 months of testosterone gel, compared with those assigned to placebo.

The men treated with testosterone showed a mean increase in noncalcified coronary artery plaque volume of 40 mm³, compared with 4 mm³ in men given the placebo gel, and a mean increase in total plaque volume of 57 mm³ with testosterone and 21 mm³ with placebo (JAMA. 2017 Feb 21;317[7]:708-16).

There were no significant differences between the groups in change to coronary artery calcium score, and there were no adverse cardiovascular events reported in either group, despite the fact that around half the participants had severe atherosclerosis at baseline.

“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning, because any limitation of the vascular lumen could be considered deleterious,” wrote Matthew J. Budoff, MD, of the Los Angeles Biomedical Research Institute, Torrance, Calif., and his coauthors. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”

However, the investigators pointed out that the trial was neither large enough nor long enough to draw conclusions about the cardiovascular risks of testosterone treatment, and they called for larger studies to explore the association.

Cognitive function

The fourth study looked at mean change in cognitive function from baseline in 493 men with a serum testosterone level less than 275 ng/dL, impaired sexual function, physical function, or vitality, and who met the criteria for age-associated memory impairment. Half the participants were assigned to 12 months of testosterone gel, and half were assigned to placebo gel (JAMA. 2017 Feb 21;317[7]:717-27).

Researchers found no significant differences between the two groups from baseline to 6 months and 12 months in mean change in delayed paragraph recall score, visual memory, executive function, or spatial ability.

“The lack of association between testosterone treatment and cognition was apparent across all cognitive domains assessed among men with [age-associated memory impairment], in spite of an increase in circulating total and free testosterone concentrations in the testosterone group to levels typical of men aged 19-40 years,” wrote Susan M. Resnick, PhD, of the National Institute on Aging, and her coauthors.

The Testosterone Trials were supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Diseases and Stroke, the National Institute of Child Health and Human Development, and AbbVie, which also provided the AndroGel, and placebo gel. Authors from the trials declared a range of funding, consultancies, and other support from the pharmaceutical industry, including AbbVie. One author declared a pending patent for a free testosterone calculator.

Testosterone treatment may have beneficial effects on unexplained anemia or bone density in men with age-related low testosterone, but at the cost of an increase in coronary artery plaque and with no benefit on cognitive function, new research suggests.

The results of four of the seven Testosterone Trials were published Feb. 21 in JAMA and JAMA Internal Medicine, adding to a growing body of research on the impact of testosterone supplementation but without finding clear evidence of an overall benefit.

In the double-blind, multicenter Anemia Trial, 788 men aged 65 years or older with average testosterone levels of less than 275 ng/dL were allocated to 12 months of testosterone gel or placebo. The group included 126 individuals with a hemoglobin level at or below 12.7 g/dL (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9540).

The study found that significantly more men who received testosterone treatment experienced increases in hemoglobin concentration of 1 g/dL or more above baseline, compared with those who received the placebo gel (54% vs. 15%; 95% CI 3.7-277.8; P = .002).

This effect was seen in men with known causes of anemia, such as myelodysplasia, iron deficiency, B₁₂ deficiency, or chronic inflammation or disease; in men with anemia of unknown case; and in men who weren’t anemic.

After 12 months, more than half of the testosterone-treated men who started the study with unexplained anemia were no longer anemic, compared with around one-quarter of the placebo-treated men (58.3% vs. 22.2%). The men treated with placebo also had lower average hemoglobin level changes, compared with those treated with testosterone.

“Increases in hemoglobin levels were positively and significantly associated with participants’ global impression of change in overall health and energy,” wrote Cindy N. Roy, PhD, of Johns Hopkins University, Baltimore, and her coauthors.

Bone mineral density

A second trial examined the effect of 12 months of testosterone gel or placebo on bone mineral density in a group of 211 men with average testosterone concentrations less than 275 ng/L (JAMA Intern Med. 2017 Feb 21. doi: 10.1001/jamainternmed.2016.9539). The treatment increased median serum concentrations of total testosterone, free testosterone, and estradiol to within the normal ranges for young men.

The study showed significantly greater increases – measured by quantitative computed tomography – with testosterone treatment, compared with placebo, in spine trabecular, spine peripheral, hip trabecular, and peripheral volumetric bone mineral density, as well as in mean estimated strength of spine trabecular bone, spine peripheral bone, and hip trabecular and peripheral bone.

For the primary outcome of mean lumbar spine trabecular volumetric bone mineral density, testosterone treatment was associated with a mean increase of 7.5%, compared with a 0.8% increase with placebo.

Researchers also noted that the magnitude of the increase in spine trabecular bone mineral density from baseline was significantly associated with changes in total testosterone and estradiol.

However, there were no significant differences in fracture rate, with six fractures reported in each group during the year of treatment. In the observation year after treatment, three fractures were reported in the testosterone arm and four in the placebo arm.

“These results are unequivocal compared with prior studies of the effect of testosterone treatment on bone in older men, in spite of treatment limited to 1 year, perhaps because the mean pretreatment testosterone level was lower and the sample size larger than in prior studies, and because the primary outcome in this trial was vBMD by QCT,” wrote Peter J. Snyder, MD, of the University of Pennsylvania, Philadelphia, and his coauthors.

Coronary artery plaque

However, a third trial – this one in 170 men with low testosterone and symptoms suggestive of hypogonadism – found significantly greater increases in noncalcified plaque volume, median total plaque volume, and median coronary artery calcification score among the 88 men assigned to 12 months of testosterone gel, compared with those assigned to placebo.

The men treated with testosterone showed a mean increase in noncalcified coronary artery plaque volume of 40 mm³, compared with 4 mm³ in men given the placebo gel, and a mean increase in total plaque volume of 57 mm³ with testosterone and 21 mm³ with placebo (JAMA. 2017 Feb 21;317[7]:708-16).

There were no significant differences between the groups in change to coronary artery calcium score, and there were no adverse cardiovascular events reported in either group, despite the fact that around half the participants had severe atherosclerosis at baseline.

“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning, because any limitation of the vascular lumen could be considered deleterious,” wrote Matthew J. Budoff, MD, of the Los Angeles Biomedical Research Institute, Torrance, Calif., and his coauthors. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”

However, the investigators pointed out that the trial was neither large enough nor long enough to draw conclusions about the cardiovascular risks of testosterone treatment, and they called for larger studies to explore the association.

Cognitive function

The fourth study looked at mean change in cognitive function from baseline in 493 men with a serum testosterone level less than 275 ng/dL, impaired sexual function, physical function, or vitality, and who met the criteria for age-associated memory impairment. Half the participants were assigned to 12 months of testosterone gel, and half were assigned to placebo gel (JAMA. 2017 Feb 21;317[7]:717-27).

Researchers found no significant differences between the two groups from baseline to 6 months and 12 months in mean change in delayed paragraph recall score, visual memory, executive function, or spatial ability.

“The lack of association between testosterone treatment and cognition was apparent across all cognitive domains assessed among men with [age-associated memory impairment], in spite of an increase in circulating total and free testosterone concentrations in the testosterone group to levels typical of men aged 19-40 years,” wrote Susan M. Resnick, PhD, of the National Institute on Aging, and her coauthors.

The Testosterone Trials were supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Diseases and Stroke, the National Institute of Child Health and Human Development, and AbbVie, which also provided the AndroGel, and placebo gel. Authors from the trials declared a range of funding, consultancies, and other support from the pharmaceutical industry, including AbbVie. One author declared a pending patent for a free testosterone calculator.

Image by James Thomson

Researchers say they have created a model that shows the step-by-step progression from normal blood cells to acute myeloid leukemia (AML).

The team generated induced pluripotent stem cell (iPSC) lines capturing disease stages that included preleukemia, low-risk myelodysplastic syndrome (MDS), high-risk MDS, and AML.

The researchers then used CRISPR/Cas9 genome editing to induce disease progression and reversal.

And they used the iPSCs to uncover disease-stage-specific effects of 2 drugs.

Eirini P. Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and her colleagues described this work in Cell Stem Cell.

The researchers first explained how they generated patient-derived iPSCs that represented familial predisposition to myeloid malignancy, low-risk and high-risk MDS, and AML.

By studying these iPSC lines, the team uncovered “a phenotypic road map of disease progression” that led to a “serially transplantable leukemia.”

“We are encouraged by the discovery that it was possible to generate potent, engraftable leukemia derived from AML induced pluripotent stem cells,” said study author Michael G. Kharas, PhD, of the Icahn School of Medicine at Mount Sinai.

The researchers also showed that they could revert a high-risk MDS iPSC line to a premalignant state by correcting a chromosome 7q deletion.

And they could force progression in a preleukemic iPSC line. The team induced progression to low-risk MDS by inactivating the second GATA2 allele and progression to high-risk MDS by deleting chromosome 7q.

“This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression,” Dr Kharas said.

The researchers reported that, ultimately, they were able to model the stepwise progression of normal cells to preleukemia and MDS by sequentially introducing genetic lesions associated with earlier and later disease stages (ASXL1 truncation and chromosome 7q deletion, respectively).

“The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before,” Dr Papapetrou said.

She added that the group’s findings provide a framework to aid investigation into disease mechanisms, events driving progression, and drug responses.

In fact, the researchers did use hematopoietic progenitor cells (HPCs) derived from their iPSCs to analyze the disease-stage-specific effects of 2 drugs—5-azacytidine and rigosertib.

The team said they found evidence to suggest that 5-azacytidine may work in low-risk MDS by affecting differentiation, and the drug’s main therapeutic action in high-risk MDS might be mediated through selective inhibition of the MDS clone.

The researchers tested rigosertib in HPCs derived from 2 AML lines (from the same patient) that captured 2 different disease stages. One line was derived from the dominant clone (del 7q), and the other was derived from a KRAS-mutated subclone.

The team found that HPCs derived from the KRAS-mutated line demonstrated “marked sensitivity” to rigosertib, but the other HPCs were “marginally affected.”

Image by James Thomson

Researchers say they have created a model that shows the step-by-step progression from normal blood cells to acute myeloid leukemia (AML).

The team generated induced pluripotent stem cell (iPSC) lines capturing disease stages that included preleukemia, low-risk myelodysplastic syndrome (MDS), high-risk MDS, and AML.

The researchers then used CRISPR/Cas9 genome editing to induce disease progression and reversal.

And they used the iPSCs to uncover disease-stage-specific effects of 2 drugs.

Eirini P. Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and her colleagues described this work in Cell Stem Cell.

The researchers first explained how they generated patient-derived iPSCs that represented familial predisposition to myeloid malignancy, low-risk and high-risk MDS, and AML.

By studying these iPSC lines, the team uncovered “a phenotypic road map of disease progression” that led to a “serially transplantable leukemia.”

“We are encouraged by the discovery that it was possible to generate potent, engraftable leukemia derived from AML induced pluripotent stem cells,” said study author Michael G. Kharas, PhD, of the Icahn School of Medicine at Mount Sinai.

The researchers also showed that they could revert a high-risk MDS iPSC line to a premalignant state by correcting a chromosome 7q deletion.

And they could force progression in a preleukemic iPSC line. The team induced progression to low-risk MDS by inactivating the second GATA2 allele and progression to high-risk MDS by deleting chromosome 7q.

“This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression,” Dr Kharas said.

The researchers reported that, ultimately, they were able to model the stepwise progression of normal cells to preleukemia and MDS by sequentially introducing genetic lesions associated with earlier and later disease stages (ASXL1 truncation and chromosome 7q deletion, respectively).

“The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before,” Dr Papapetrou said.

She added that the group’s findings provide a framework to aid investigation into disease mechanisms, events driving progression, and drug responses.

In fact, the researchers did use hematopoietic progenitor cells (HPCs) derived from their iPSCs to analyze the disease-stage-specific effects of 2 drugs—5-azacytidine and rigosertib.

The team said they found evidence to suggest that 5-azacytidine may work in low-risk MDS by affecting differentiation, and the drug’s main therapeutic action in high-risk MDS might be mediated through selective inhibition of the MDS clone.

The researchers tested rigosertib in HPCs derived from 2 AML lines (from the same patient) that captured 2 different disease stages. One line was derived from the dominant clone (del 7q), and the other was derived from a KRAS-mutated subclone.

The team found that HPCs derived from the KRAS-mutated line demonstrated “marked sensitivity” to rigosertib, but the other HPCs were “marginally affected.”

Image by James Thomson

Researchers say they have created a model that shows the step-by-step progression from normal blood cells to acute myeloid leukemia (AML).

The team generated induced pluripotent stem cell (iPSC) lines capturing disease stages that included preleukemia, low-risk myelodysplastic syndrome (MDS), high-risk MDS, and AML.

The researchers then used CRISPR/Cas9 genome editing to induce disease progression and reversal.

And they used the iPSCs to uncover disease-stage-specific effects of 2 drugs.

Eirini P. Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and her colleagues described this work in Cell Stem Cell.

The researchers first explained how they generated patient-derived iPSCs that represented familial predisposition to myeloid malignancy, low-risk and high-risk MDS, and AML.

By studying these iPSC lines, the team uncovered “a phenotypic road map of disease progression” that led to a “serially transplantable leukemia.”

“We are encouraged by the discovery that it was possible to generate potent, engraftable leukemia derived from AML induced pluripotent stem cells,” said study author Michael G. Kharas, PhD, of the Icahn School of Medicine at Mount Sinai.

The researchers also showed that they could revert a high-risk MDS iPSC line to a premalignant state by correcting a chromosome 7q deletion.

And they could force progression in a preleukemic iPSC line. The team induced progression to low-risk MDS by inactivating the second GATA2 allele and progression to high-risk MDS by deleting chromosome 7q.

“This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression,” Dr Kharas said.

The researchers reported that, ultimately, they were able to model the stepwise progression of normal cells to preleukemia and MDS by sequentially introducing genetic lesions associated with earlier and later disease stages (ASXL1 truncation and chromosome 7q deletion, respectively).

“The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before,” Dr Papapetrou said.

She added that the group’s findings provide a framework to aid investigation into disease mechanisms, events driving progression, and drug responses.

In fact, the researchers did use hematopoietic progenitor cells (HPCs) derived from their iPSCs to analyze the disease-stage-specific effects of 2 drugs—5-azacytidine and rigosertib.

The team said they found evidence to suggest that 5-azacytidine may work in low-risk MDS by affecting differentiation, and the drug’s main therapeutic action in high-risk MDS might be mediated through selective inhibition of the MDS clone.

The researchers tested rigosertib in HPCs derived from 2 AML lines (from the same patient) that captured 2 different disease stages. One line was derived from the dominant clone (del 7q), and the other was derived from a KRAS-mutated subclone.

The team found that HPCs derived from the KRAS-mutated line demonstrated “marked sensitivity” to rigosertib, but the other HPCs were “marginally affected.”

Photo by Tiffany Dawn Nicholson

Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.

The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.

But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.

The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.

Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.

The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.

Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.

The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.

This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.

This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.

“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.

“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”

Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.

“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”

After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.

Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.

Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.

“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.

“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”

The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.

Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.

“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.

He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.

“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”

Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.

“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.

He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide.

Photo by Tiffany Dawn Nicholson

Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.

The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.

But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.

The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.

Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.

The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.

Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.

The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.

This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.

This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.

“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.

“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”

Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.

“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”

After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.

Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.

Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.

“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.

“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”

The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.

Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.

“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.

He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.

“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”

Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.

“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.

He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide.

Photo by Tiffany Dawn Nicholson

Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.

The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.

But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.

The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.

Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.

The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.

Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.

The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.

This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.

This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.

“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.

“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”

Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.

“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”

After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.

Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.

Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.

“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.

“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”

The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.

Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.

“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.

He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.

“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”

Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.

“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.

He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

Population-based surveillance data has revealed patterns of emergency department (ED) visits among Californians with sickle cell disease (SCD).

Previous research suggested that between one-half and two-thirds of SCD patients’ ED visits end in a discharge from the ED, called a treat-and-release visit.

The remainder result in admission to a hospital or other treatment facility.

The purpose of the current study was to use data from the Sickle Cell Data Collection program to describe patterns of ED use for treat-and-release visits by California’s SCD population and compare these new findings with results of previous studies.

The current study was published in Pediatric Blood and Cancer.

Researchers looked at ED and hospital discharge data in California from 2005 to 2014. This included 4636 patients with SCD.

The data showed that 88% of patients had 1 or more treat-and-release ED visits during the 10-year study period.

This group of 4100 patients had 90,904 treat-and-release ED visits. The average number of visits each year was 2.1 (rage, 0-185).

In a single year (2005):

• 53% of patients had no treat-and-release ED visits (no ED use)
• 35% had between 1 and 3 visits (low ED use)
• 9% had between 4 and 10 visits (medium ED use)
• 3% had 11 or more visits (high ED use).

The youngest patients (age 0 to 9.9) and the oldest patients (80 and older) were the least likely to have at least 1 treat-and-release ED visit.

The proportion of patients with at least 1 ED visit over the study period was:

• 68% among patients age 0 to 9.9 at the close of the study
• 80% among patients age 10 to 19.9
• 92% among patients age 20 to 29.9
• 94% among patients age 30 to 39.9
• 93% among patients age 40 to 49.9
• 92% among patients age 50 to 59.9
• 92% among patients age 60 to 69.9
• 85% among patients age 70 to 79.9
• 73% among patients age 80 and older.

The researchers said this study highlights the utility of a multisource, longitudinal data collection effort for SCD. And further study of patients with the highest ED utilization may highlight areas where changes could improve and extend the lives of patients with SCD.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

Population-based surveillance data has revealed patterns of emergency department (ED) visits among Californians with sickle cell disease (SCD).

Previous research suggested that between one-half and two-thirds of SCD patients’ ED visits end in a discharge from the ED, called a treat-and-release visit.

The remainder result in admission to a hospital or other treatment facility.

The purpose of the current study was to use data from the Sickle Cell Data Collection program to describe patterns of ED use for treat-and-release visits by California’s SCD population and compare these new findings with results of previous studies.

The current study was published in Pediatric Blood and Cancer.

Researchers looked at ED and hospital discharge data in California from 2005 to 2014. This included 4636 patients with SCD.

The data showed that 88% of patients had 1 or more treat-and-release ED visits during the 10-year study period.

This group of 4100 patients had 90,904 treat-and-release ED visits. The average number of visits each year was 2.1 (rage, 0-185).

In a single year (2005):

• 53% of patients had no treat-and-release ED visits (no ED use)
• 35% had between 1 and 3 visits (low ED use)
• 9% had between 4 and 10 visits (medium ED use)
• 3% had 11 or more visits (high ED use).

The youngest patients (age 0 to 9.9) and the oldest patients (80 and older) were the least likely to have at least 1 treat-and-release ED visit.

The proportion of patients with at least 1 ED visit over the study period was:

• 68% among patients age 0 to 9.9 at the close of the study
• 80% among patients age 10 to 19.9
• 92% among patients age 20 to 29.9
• 94% among patients age 30 to 39.9
• 93% among patients age 40 to 49.9
• 92% among patients age 50 to 59.9
• 92% among patients age 60 to 69.9
• 85% among patients age 70 to 79.9
• 73% among patients age 80 and older.

The researchers said this study highlights the utility of a multisource, longitudinal data collection effort for SCD. And further study of patients with the highest ED utilization may highlight areas where changes could improve and extend the lives of patients with SCD.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

Population-based surveillance data has revealed patterns of emergency department (ED) visits among Californians with sickle cell disease (SCD).

Previous research suggested that between one-half and two-thirds of SCD patients’ ED visits end in a discharge from the ED, called a treat-and-release visit.

The remainder result in admission to a hospital or other treatment facility.

The purpose of the current study was to use data from the Sickle Cell Data Collection program to describe patterns of ED use for treat-and-release visits by California’s SCD population and compare these new findings with results of previous studies.

The current study was published in Pediatric Blood and Cancer.

Researchers looked at ED and hospital discharge data in California from 2005 to 2014. This included 4636 patients with SCD.

The data showed that 88% of patients had 1 or more treat-and-release ED visits during the 10-year study period.

This group of 4100 patients had 90,904 treat-and-release ED visits. The average number of visits each year was 2.1 (rage, 0-185).

In a single year (2005):

• 53% of patients had no treat-and-release ED visits (no ED use)
• 35% had between 1 and 3 visits (low ED use)
• 9% had between 4 and 10 visits (medium ED use)
• 3% had 11 or more visits (high ED use).

The youngest patients (age 0 to 9.9) and the oldest patients (80 and older) were the least likely to have at least 1 treat-and-release ED visit.

The proportion of patients with at least 1 ED visit over the study period was:

• 68% among patients age 0 to 9.9 at the close of the study
• 80% among patients age 10 to 19.9
• 92% among patients age 20 to 29.9
• 94% among patients age 30 to 39.9
• 93% among patients age 40 to 49.9
• 92% among patients age 50 to 59.9
• 92% among patients age 60 to 69.9
• 85% among patients age 70 to 79.9
• 73% among patients age 80 and older.

The researchers said this study highlights the utility of a multisource, longitudinal data collection effort for SCD. And further study of patients with the highest ED utilization may highlight areas where changes could improve and extend the lives of patients with SCD.