ORLANDO – Stored red blood cells kept for longer than a few weeks do not impair outcomes or harm the patients who receive them, Dr. Christine Cserti-Gazdewich reported at the annual meeting of the American Society of Hematology.

In a randomized clinical trial conducted in Kanpala, Uganda, where severe anemia with lactic acidosis is common, children who received RBCs that had been stored from 25-35 days had outcomes that were not inferior to those of children who received RBCs delivered within 10 days of collection. The findings have significant, positive implications for countries and geographic regions where there are chronic shortages of blood products, said Dr. Cserti-Gazdewich, of Toronto General Hospital.

ORLANDO – Stored red blood cells kept for longer than a few weeks do not impair outcomes or harm the patients who receive them, Dr. Christine Cserti-Gazdewich reported at the annual meeting of the American Society of Hematology.

In a randomized clinical trial conducted in Kanpala, Uganda, where severe anemia with lactic acidosis is common, children who received RBCs that had been stored from 25-35 days had outcomes that were not inferior to those of children who received RBCs delivered within 10 days of collection. The findings have significant, positive implications for countries and geographic regions where there are chronic shortages of blood products, said Dr. Cserti-Gazdewich, of Toronto General Hospital.

ORLANDO – Stored red blood cells kept for longer than a few weeks do not impair outcomes or harm the patients who receive them, Dr. Christine Cserti-Gazdewich reported at the annual meeting of the American Society of Hematology.

In a randomized clinical trial conducted in Kanpala, Uganda, where severe anemia with lactic acidosis is common, children who received RBCs that had been stored from 25-35 days had outcomes that were not inferior to those of children who received RBCs delivered within 10 days of collection. The findings have significant, positive implications for countries and geographic regions where there are chronic shortages of blood products, said Dr. Cserti-Gazdewich, of Toronto General Hospital.

ORLANDO – Oral hydroxyurea is as good as chronic red blood cell transfusions for prevention of primary stroke in children at high-risk for this devastating complication of sickle cell disease, results of the TWiTCH study show.

No child suffered a stroke with either hydroxyurea or monthly transfusions and transcranial doppler (TCD) velocities were maintained in both arms.

The study was stopped early, however, after noninferiority was shown for the primary end point of TCD mean velocities on the index side at 24 months, with a post-hoc analysis suggesting hydroxyurea may even be superior, study author Dr. Russell E. Ware, director of hematology at Cincinnati (Ohio) Children’s Hospital Medical Center, reported during the plenary session at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

“Hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke,” he said during a press briefing.

The final mean TCD velocities were 143 cm/second in the transfusion arm and 138 cm/sec in the hydroxyurea arm, resulting in P values of 8.82 x 10^-16 for non-inferiority by intention-to-treat analysis and 0.023 for superiority in a post-hoc analysis.

Hydroxyurea also had the added benefit of improving iron overload status more than monthly transfusions based on a greater average change in serum ferritin (-1,085 ng/mL vs. -38 ng/mL; P less than .001) and liver iron concentrations (-1.9 mg/g vs. +2.4 mg/g; P = .001), according to their report.

Press briefing moderator Dr. Alexis Thompson, of the Ann & Robert H. Lurie Children’s Hospital of Chicago, commented, “This truly is one of the abstracts that are being presenting at the meeting today that can be defined as practice changing. There are many families who have great difficulty accepting the reality, prior to the TWiTCH study, of their children having to be transfused lifelong.”

Strokes occur in up to 10% of children with sickle cell disease (SCD). Transfusions are effective for stroke prophylaxis in this setting, but have to be continued lifelong and can lead to iron overload and other complications.

Based on the participating sites, at least 80% of children with abnormal TCD velocities currently on blood transfusions to prevent stroke would be eligible for treatment with hydroxyurea, Dr. Ware said.

Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and was approved more than a decade ago to ameliorate the acute and chronic complications of SCD. Its use could provide dramatic cost savings for families since a transfusion costs about $1,000 to $2,000 every month, whereas hydroxyurea costs less than a dollar a day, Dr. Ware said in an interview.

TWiTCH (TCD with Transfusions Changing to Hydroxyurea) was conducted at 26 pediatric programs and used TCD to identify 121 children with SCD who were at elevated risk of stroke based on abnormally high cerebral artery flow velocities of at least 200 cm/sec. The children were evenly randomized to 24 months of treatment. TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators blinded to the results. All children had received transfusions for at least 12 months, but had not developed severe vasculopathy.

The transfusion arm was maintained at a target hemoglobin S level of less than 30% and chelation used to manage elevated liver concentrations. Transfusions were allowed in the hydroxyurea arm until a stable maximum tolerated dose (MTD) of hydroxyurea was reached, and were then replaced by serial phlebotomy to reduce iron overload. The MTD was reached after 6 months at an average dose of about 25 mg/kg/day.

The transfusion overlap with hydroxyurea was designed as a safety measure to avoid strokes if monthly transfusions were abruptly discontinued in the hydroxyurea arm before the children had time to achieve MTD.

“The fact that that overlap was about 6 months and the fact we had about 24 months of follow-up tracking the TCD velocities over time, we feel that doesn’t affect the end statistical analysis,” Dr. Ware said.

As for whether hydroxyurea is superior to monthly transfusions, he noted that the trial was not designed for superiority and superiority was seen in a post-hoc analysis. “What we can say with certainty is that it’s non-inferior to the standard treatment,” Dr. Ware said.

The final analysis was based on 42 patients randomized to the transfusion arm who completed all 24 months of treatment, 11 with truncated treatment, and 8 withdrawals, and 41 patients assigned to the hydroxyurea arm who completed all treatment, 13 with truncated treatment and 6 withdrawals.

Sickle cell-related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15), but none were related to the study drug or procedures.

There were 29 new centrally adjudicated neurological events including 3 transient ischemic attacks in each arm. In the transfusion arm, one child was withdrawn per protocol after developing TCD velocities exceeding 240 cm/sec and a second developed new vasculopathy. The safety of long-term hydroxyurea has been established in multiple pediatric studies, Dr. Ware said.

TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.

[email protected]

ORLANDO – Oral hydroxyurea is as good as chronic red blood cell transfusions for prevention of primary stroke in children at high-risk for this devastating complication of sickle cell disease, results of the TWiTCH study show.

No child suffered a stroke with either hydroxyurea or monthly transfusions and transcranial doppler (TCD) velocities were maintained in both arms.

The study was stopped early, however, after noninferiority was shown for the primary end point of TCD mean velocities on the index side at 24 months, with a post-hoc analysis suggesting hydroxyurea may even be superior, study author Dr. Russell E. Ware, director of hematology at Cincinnati (Ohio) Children’s Hospital Medical Center, reported during the plenary session at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

“Hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke,” he said during a press briefing.

The final mean TCD velocities were 143 cm/second in the transfusion arm and 138 cm/sec in the hydroxyurea arm, resulting in P values of 8.82 x 10^-16 for non-inferiority by intention-to-treat analysis and 0.023 for superiority in a post-hoc analysis.

Hydroxyurea also had the added benefit of improving iron overload status more than monthly transfusions based on a greater average change in serum ferritin (-1,085 ng/mL vs. -38 ng/mL; P less than .001) and liver iron concentrations (-1.9 mg/g vs. +2.4 mg/g; P = .001), according to their report.

Press briefing moderator Dr. Alexis Thompson, of the Ann & Robert H. Lurie Children’s Hospital of Chicago, commented, “This truly is one of the abstracts that are being presenting at the meeting today that can be defined as practice changing. There are many families who have great difficulty accepting the reality, prior to the TWiTCH study, of their children having to be transfused lifelong.”

Strokes occur in up to 10% of children with sickle cell disease (SCD). Transfusions are effective for stroke prophylaxis in this setting, but have to be continued lifelong and can lead to iron overload and other complications.

Based on the participating sites, at least 80% of children with abnormal TCD velocities currently on blood transfusions to prevent stroke would be eligible for treatment with hydroxyurea, Dr. Ware said.

Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and was approved more than a decade ago to ameliorate the acute and chronic complications of SCD. Its use could provide dramatic cost savings for families since a transfusion costs about $1,000 to $2,000 every month, whereas hydroxyurea costs less than a dollar a day, Dr. Ware said in an interview.

TWiTCH (TCD with Transfusions Changing to Hydroxyurea) was conducted at 26 pediatric programs and used TCD to identify 121 children with SCD who were at elevated risk of stroke based on abnormally high cerebral artery flow velocities of at least 200 cm/sec. The children were evenly randomized to 24 months of treatment. TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators blinded to the results. All children had received transfusions for at least 12 months, but had not developed severe vasculopathy.

The transfusion arm was maintained at a target hemoglobin S level of less than 30% and chelation used to manage elevated liver concentrations. Transfusions were allowed in the hydroxyurea arm until a stable maximum tolerated dose (MTD) of hydroxyurea was reached, and were then replaced by serial phlebotomy to reduce iron overload. The MTD was reached after 6 months at an average dose of about 25 mg/kg/day.

The transfusion overlap with hydroxyurea was designed as a safety measure to avoid strokes if monthly transfusions were abruptly discontinued in the hydroxyurea arm before the children had time to achieve MTD.

“The fact that that overlap was about 6 months and the fact we had about 24 months of follow-up tracking the TCD velocities over time, we feel that doesn’t affect the end statistical analysis,” Dr. Ware said.

As for whether hydroxyurea is superior to monthly transfusions, he noted that the trial was not designed for superiority and superiority was seen in a post-hoc analysis. “What we can say with certainty is that it’s non-inferior to the standard treatment,” Dr. Ware said.

The final analysis was based on 42 patients randomized to the transfusion arm who completed all 24 months of treatment, 11 with truncated treatment, and 8 withdrawals, and 41 patients assigned to the hydroxyurea arm who completed all treatment, 13 with truncated treatment and 6 withdrawals.

Sickle cell-related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15), but none were related to the study drug or procedures.

There were 29 new centrally adjudicated neurological events including 3 transient ischemic attacks in each arm. In the transfusion arm, one child was withdrawn per protocol after developing TCD velocities exceeding 240 cm/sec and a second developed new vasculopathy. The safety of long-term hydroxyurea has been established in multiple pediatric studies, Dr. Ware said.

TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.

[email protected]

ORLANDO – Oral hydroxyurea is as good as chronic red blood cell transfusions for prevention of primary stroke in children at high-risk for this devastating complication of sickle cell disease, results of the TWiTCH study show.

No child suffered a stroke with either hydroxyurea or monthly transfusions and transcranial doppler (TCD) velocities were maintained in both arms.

The study was stopped early, however, after noninferiority was shown for the primary end point of TCD mean velocities on the index side at 24 months, with a post-hoc analysis suggesting hydroxyurea may even be superior, study author Dr. Russell E. Ware, director of hematology at Cincinnati (Ohio) Children’s Hospital Medical Center, reported during the plenary session at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

“Hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke,” he said during a press briefing.

The final mean TCD velocities were 143 cm/second in the transfusion arm and 138 cm/sec in the hydroxyurea arm, resulting in P values of 8.82 x 10^-16 for non-inferiority by intention-to-treat analysis and 0.023 for superiority in a post-hoc analysis.

Hydroxyurea also had the added benefit of improving iron overload status more than monthly transfusions based on a greater average change in serum ferritin (-1,085 ng/mL vs. -38 ng/mL; P less than .001) and liver iron concentrations (-1.9 mg/g vs. +2.4 mg/g; P = .001), according to their report.

Press briefing moderator Dr. Alexis Thompson, of the Ann & Robert H. Lurie Children’s Hospital of Chicago, commented, “This truly is one of the abstracts that are being presenting at the meeting today that can be defined as practice changing. There are many families who have great difficulty accepting the reality, prior to the TWiTCH study, of their children having to be transfused lifelong.”

Strokes occur in up to 10% of children with sickle cell disease (SCD). Transfusions are effective for stroke prophylaxis in this setting, but have to be continued lifelong and can lead to iron overload and other complications.

Based on the participating sites, at least 80% of children with abnormal TCD velocities currently on blood transfusions to prevent stroke would be eligible for treatment with hydroxyurea, Dr. Ware said.

Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and was approved more than a decade ago to ameliorate the acute and chronic complications of SCD. Its use could provide dramatic cost savings for families since a transfusion costs about $1,000 to $2,000 every month, whereas hydroxyurea costs less than a dollar a day, Dr. Ware said in an interview.

TWiTCH (TCD with Transfusions Changing to Hydroxyurea) was conducted at 26 pediatric programs and used TCD to identify 121 children with SCD who were at elevated risk of stroke based on abnormally high cerebral artery flow velocities of at least 200 cm/sec. The children were evenly randomized to 24 months of treatment. TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators blinded to the results. All children had received transfusions for at least 12 months, but had not developed severe vasculopathy.

The transfusion arm was maintained at a target hemoglobin S level of less than 30% and chelation used to manage elevated liver concentrations. Transfusions were allowed in the hydroxyurea arm until a stable maximum tolerated dose (MTD) of hydroxyurea was reached, and were then replaced by serial phlebotomy to reduce iron overload. The MTD was reached after 6 months at an average dose of about 25 mg/kg/day.

The transfusion overlap with hydroxyurea was designed as a safety measure to avoid strokes if monthly transfusions were abruptly discontinued in the hydroxyurea arm before the children had time to achieve MTD.

“The fact that that overlap was about 6 months and the fact we had about 24 months of follow-up tracking the TCD velocities over time, we feel that doesn’t affect the end statistical analysis,” Dr. Ware said.

As for whether hydroxyurea is superior to monthly transfusions, he noted that the trial was not designed for superiority and superiority was seen in a post-hoc analysis. “What we can say with certainty is that it’s non-inferior to the standard treatment,” Dr. Ware said.

The final analysis was based on 42 patients randomized to the transfusion arm who completed all 24 months of treatment, 11 with truncated treatment, and 8 withdrawals, and 41 patients assigned to the hydroxyurea arm who completed all treatment, 13 with truncated treatment and 6 withdrawals.

Sickle cell-related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15), but none were related to the study drug or procedures.

There were 29 new centrally adjudicated neurological events including 3 transient ischemic attacks in each arm. In the transfusion arm, one child was withdrawn per protocol after developing TCD velocities exceeding 240 cm/sec and a second developed new vasculopathy. The safety of long-term hydroxyurea has been established in multiple pediatric studies, Dr. Ware said.

TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.

[email protected]

ORLANDO – Children with chronic immune thrombocytopenia (ITP) have an increased frequency of damaging variants in genes associated with cellular immunity, notably IFNA17 and IFNLR1, based on the results of whole genome sequencing.

The links to IFNA17 and IFNLR1 genes, which are involved in T cell pathways, remain significant when patients are stratified according to disease severity, Dr. Jenny M. Despotovic reported at the annual meeting of the American Sociey of Hematology. The finding is further evidence for the role of T cell abnormalities in the pathophysiology of chronic ITP.

These may be important candidate genes involved in immune regulation and in sustained autoimmunity, which appears to be due to generalized immune dysregulation that includes altered T cell balance with a shift toward immune activation (increased Th1/Th2 ratio) as well as decreased number and impaired function of regulatory T cells, said Dr. Despotovic, of Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston.

In their study, Dr. Despotovic and her colleagues performed whole exome sequencing on 262 samples with robust phenotype data from children with chronic ITP in the North American Chronic ITP Registry and the Platelet Disorders Center at the Weill-Cornell Medical Center. All but three patients were less than 20 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, and 7% had other autoimmune disorders.

To identify candidate genes associated with ITP susceptibility, sequencing data were compared for 172 ITP cases of European American ancestry and 5,664 controls of European American ancestry with platelet levels over 150 x 10⁹/L in the Atherosclerosis Risk in Communities (ARIC) Study. In a separate analysis, phenotype data for ITP cases were reviewed and cases were stratified by disease severity according to the need for second line treatment.

A significant increase in the frequency of several damaging variants were identified in genes in the ITP cohort. The most significant associations were detected in the IFNA17 gene, which is involved in transforming growth factor beta secretion and could affect number and function of regulatory T cells.

IFNA17 rs9298814 was identified in 26% of cases in the ITP cohort compared to less than 0.01% of controls. In all, 43% of ITP patients had at a presumed deleterious variant of IFNA17.

IFNA17 gene variants remained significant in the most severely affected patients, specifically those requiring second line therapy, providing further evidence for this gene’s functional relevance in the pathogenesis and pathophysiology of ITP, Dr. Despotovic said.

Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained an increased frequency of variants in the European American ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy.

Analysis of this large cohort did not validate any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP, she added.

[email protected]

On Twitter @maryjodales

ORLANDO – Children with chronic immune thrombocytopenia (ITP) have an increased frequency of damaging variants in genes associated with cellular immunity, notably IFNA17 and IFNLR1, based on the results of whole genome sequencing.

The links to IFNA17 and IFNLR1 genes, which are involved in T cell pathways, remain significant when patients are stratified according to disease severity, Dr. Jenny M. Despotovic reported at the annual meeting of the American Sociey of Hematology. The finding is further evidence for the role of T cell abnormalities in the pathophysiology of chronic ITP.

These may be important candidate genes involved in immune regulation and in sustained autoimmunity, which appears to be due to generalized immune dysregulation that includes altered T cell balance with a shift toward immune activation (increased Th1/Th2 ratio) as well as decreased number and impaired function of regulatory T cells, said Dr. Despotovic, of Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston.

In their study, Dr. Despotovic and her colleagues performed whole exome sequencing on 262 samples with robust phenotype data from children with chronic ITP in the North American Chronic ITP Registry and the Platelet Disorders Center at the Weill-Cornell Medical Center. All but three patients were less than 20 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, and 7% had other autoimmune disorders.

To identify candidate genes associated with ITP susceptibility, sequencing data were compared for 172 ITP cases of European American ancestry and 5,664 controls of European American ancestry with platelet levels over 150 x 10⁹/L in the Atherosclerosis Risk in Communities (ARIC) Study. In a separate analysis, phenotype data for ITP cases were reviewed and cases were stratified by disease severity according to the need for second line treatment.

A significant increase in the frequency of several damaging variants were identified in genes in the ITP cohort. The most significant associations were detected in the IFNA17 gene, which is involved in transforming growth factor beta secretion and could affect number and function of regulatory T cells.

IFNA17 rs9298814 was identified in 26% of cases in the ITP cohort compared to less than 0.01% of controls. In all, 43% of ITP patients had at a presumed deleterious variant of IFNA17.

IFNA17 gene variants remained significant in the most severely affected patients, specifically those requiring second line therapy, providing further evidence for this gene’s functional relevance in the pathogenesis and pathophysiology of ITP, Dr. Despotovic said.

Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained an increased frequency of variants in the European American ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy.

Analysis of this large cohort did not validate any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP, she added.

[email protected]

On Twitter @maryjodales

ORLANDO – Children with chronic immune thrombocytopenia (ITP) have an increased frequency of damaging variants in genes associated with cellular immunity, notably IFNA17 and IFNLR1, based on the results of whole genome sequencing.

The links to IFNA17 and IFNLR1 genes, which are involved in T cell pathways, remain significant when patients are stratified according to disease severity, Dr. Jenny M. Despotovic reported at the annual meeting of the American Sociey of Hematology. The finding is further evidence for the role of T cell abnormalities in the pathophysiology of chronic ITP.

These may be important candidate genes involved in immune regulation and in sustained autoimmunity, which appears to be due to generalized immune dysregulation that includes altered T cell balance with a shift toward immune activation (increased Th1/Th2 ratio) as well as decreased number and impaired function of regulatory T cells, said Dr. Despotovic, of Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston.

In their study, Dr. Despotovic and her colleagues performed whole exome sequencing on 262 samples with robust phenotype data from children with chronic ITP in the North American Chronic ITP Registry and the Platelet Disorders Center at the Weill-Cornell Medical Center. All but three patients were less than 20 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, and 7% had other autoimmune disorders.

To identify candidate genes associated with ITP susceptibility, sequencing data were compared for 172 ITP cases of European American ancestry and 5,664 controls of European American ancestry with platelet levels over 150 x 10⁹/L in the Atherosclerosis Risk in Communities (ARIC) Study. In a separate analysis, phenotype data for ITP cases were reviewed and cases were stratified by disease severity according to the need for second line treatment.

A significant increase in the frequency of several damaging variants were identified in genes in the ITP cohort. The most significant associations were detected in the IFNA17 gene, which is involved in transforming growth factor beta secretion and could affect number and function of regulatory T cells.

IFNA17 rs9298814 was identified in 26% of cases in the ITP cohort compared to less than 0.01% of controls. In all, 43% of ITP patients had at a presumed deleterious variant of IFNA17.

IFNA17 gene variants remained significant in the most severely affected patients, specifically those requiring second line therapy, providing further evidence for this gene’s functional relevance in the pathogenesis and pathophysiology of ITP, Dr. Despotovic said.

Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained an increased frequency of variants in the European American ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy.

Analysis of this large cohort did not validate any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP, she added.

[email protected]

On Twitter @maryjodales

ORLANDO – Variants in mesenchymal stem cell genes that are important to bone and fat differentiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukemia, Dr. Seth E. Karol, of St. Jude Children’s Research Hospital in Memphis, reported at the annual meeting of the American Society of Hematology.

Mary Jo Dales

In a second study of children with ALL, Dr. Peter D. Cole, of Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture.

The pathophysiology of bony morbidity differs depending on the patient’s age, Dr. Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.”

Bony morbidity is more common in children over age 10 with ALL, and related to exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10-20 years old.

However, children under 10 make up 75% of new pediatric ALL diagnoses, Dr. Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases.

In Dr. Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.

Mary Jo Dales

The research targeted common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate.

Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures.

Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thymidylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes.

Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; P=0.019).

Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or RBC folate at any time point during therapy.

In the study reported by Dr. Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol.

Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Genes associated with the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways.

Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data.

Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways.

“Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3-6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr. Karol reported.

Dr. Cole and Dr. Karol had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

ORLANDO – Variants in mesenchymal stem cell genes that are important to bone and fat differentiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukemia, Dr. Seth E. Karol, of St. Jude Children’s Research Hospital in Memphis, reported at the annual meeting of the American Society of Hematology.

Mary Jo Dales

In a second study of children with ALL, Dr. Peter D. Cole, of Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture.

The pathophysiology of bony morbidity differs depending on the patient’s age, Dr. Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.”

Bony morbidity is more common in children over age 10 with ALL, and related to exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10-20 years old.

However, children under 10 make up 75% of new pediatric ALL diagnoses, Dr. Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases.

In Dr. Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.

Mary Jo Dales

The research targeted common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate.

Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures.

Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thymidylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes.

Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; P=0.019).

Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or RBC folate at any time point during therapy.

In the study reported by Dr. Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol.

Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Genes associated with the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways.

Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data.

Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways.

“Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3-6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr. Karol reported.

Dr. Cole and Dr. Karol had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

ORLANDO – Variants in mesenchymal stem cell genes that are important to bone and fat differentiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukemia, Dr. Seth E. Karol, of St. Jude Children’s Research Hospital in Memphis, reported at the annual meeting of the American Society of Hematology.

Mary Jo Dales

In a second study of children with ALL, Dr. Peter D. Cole, of Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture.

The pathophysiology of bony morbidity differs depending on the patient’s age, Dr. Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.”

Bony morbidity is more common in children over age 10 with ALL, and related to exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10-20 years old.

However, children under 10 make up 75% of new pediatric ALL diagnoses, Dr. Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases.

In Dr. Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.

Mary Jo Dales

The research targeted common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate.

Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures.

Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thymidylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes.

Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; P=0.019).

Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or RBC folate at any time point during therapy.

In the study reported by Dr. Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol.

Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Genes associated with the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways.

Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data.

Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways.

“Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3-6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr. Karol reported.

Dr. Cole and Dr. Karol had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

ORLANDO – Older patients with x-linked severe combined immunodeficiency syndrome (SCID-X1) treated initially with haploidentical stem cell transplantation without conditioning have impaired immunity and experience severe, life-long morbidities. Dr. Harry L. Malech, chief of the Laboratory of Host Defenses and Chief, Genetic Immunotherapy Section, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md., discusses how investigators at the U.S. NAID are treating autologous CD34 cells from patients with SCID-X1 with a lentiviral vector that transduced the cells with normal copies of the gene which in its mutated form causes SCID-X1. In early trials, they have been able to significantly improve immune function in some patients without an apparent increase in risk for malignancies, a common problem with earlier gene therapies.

ORLANDO – Older patients with x-linked severe combined immunodeficiency syndrome (SCID-X1) treated initially with haploidentical stem cell transplantation without conditioning have impaired immunity and experience severe, life-long morbidities. Dr. Harry L. Malech, chief of the Laboratory of Host Defenses and Chief, Genetic Immunotherapy Section, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md., discusses how investigators at the U.S. NAID are treating autologous CD34 cells from patients with SCID-X1 with a lentiviral vector that transduced the cells with normal copies of the gene which in its mutated form causes SCID-X1. In early trials, they have been able to significantly improve immune function in some patients without an apparent increase in risk for malignancies, a common problem with earlier gene therapies.

ORLANDO – Older patients with x-linked severe combined immunodeficiency syndrome (SCID-X1) treated initially with haploidentical stem cell transplantation without conditioning have impaired immunity and experience severe, life-long morbidities. Dr. Harry L. Malech, chief of the Laboratory of Host Defenses and Chief, Genetic Immunotherapy Section, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md., discusses how investigators at the U.S. NAID are treating autologous CD34 cells from patients with SCID-X1 with a lentiviral vector that transduced the cells with normal copies of the gene which in its mutated form causes SCID-X1. In early trials, they have been able to significantly improve immune function in some patients without an apparent increase in risk for malignancies, a common problem with earlier gene therapies.

ORLANDO – Pill containers are not known for eloquence, but they tell a disturbing tale of patient over-reporting of adherence to essential leukemia maintenance therapy.

Among 416 children with acute lymphoblastic leukemia (ALL) in first remission, the number of days patients or their guardians reported that the child took his/her daily oral 6-mercaptopurine (6MP) for maintenance was significantly higher than the number of days the pill bottles were opened, as reported by an electronic medication management system.

“Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education,” said Dr. Wendy Landier from the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham.

The results suggest that patient self-reports of adherence to 6MP oral maintenance therapy may be unreliable, and should be taken with a grain of salt, Dr. Landier said in a briefing at the American Society of Hematology annual meeting.

The investigators had previously reported that poor adherence to oral 6MP maintenance therapy was associated with a nealy four-fold increased risk for relapse (JCO 30[17]:2094-101, Blood 124[15]:2345-53).

To better understand why some patients are poorly adherent to 6MP maintenance therapy, the investigator provided 416 children with ALL in first remission with pill containers equipped with a Medication Event Management System (MEMS) that electronically recorded the dates and times that each pill bottle was opened over a 16-week period. Patients age 12 and older or the parents/guardians of younger children were also asked to report the date and time of each daily oral dose at the end of each 28-day study month.

The authors collected and evaluated a total of 1344 patient-months of self-report and MEMS data, compared the records, and stratified patients as either “perfect reporters”, whose self-reports matched the objective MEMS data; “over-reporters”, who self-report exceeded the MEMS data on 5 or more days per month for more than half of study months, and “others.”The median patient age at study entry was 6 years (range 2 to 20 years).

The authors reported in their study that 40.4% of patients were not adherent to oral 6MP therapy, as evidence by a mismatch between self-report and objective (MEMS) reporting.

The overall adjusted mean number of self-reported days per month that patients took their pills ranged from a low of 25.8+5.3 to a high of 26.1+4.5. The pill bottles, however, told a different tale, reporting that they had been opened from a low of 22.8 ± 6.4 to a high of 25.4 ± 4.5 days per month.

Month-by-month correlations between self-report and MEMS 0.36 to 0.58, and were all statistically significant.

In logistic regression models adjusted for thiopurine methyltransferase (TMPT) genotype, 6MP dose intensity, and 6-thiogaunine levels in red cells, significant predictors for over-reporting included older age, with an odds ratio (OR) of 1.07 for every 1-year increase in age (P = .04); Hispanic origin (OR 2.4, P = .02); Asian origin, (OR 3.1 P = .02; African-American origin (OR 5.3, P < .001); paternal education level lower than college (OR 2.1, P = .02); and 6MP non-adherence (OR 8.6, P < .0001).

Dr. Landier noted that 78.6% of over-reporters were non-adherent, compared with only 2% of perfect reporters.

“The real importance of this paper from my perspective is this: there is a famous quote that if the patient doesn’t take the medication it can’t work and in an era where we’re trying to improve the care of patients, one of the things we oftentimes forget that if the medication isn’t being taken, the patient can’t get better from it,” said Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster University in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was supported by grants from the National Institutes of Health and from St. Baldrick’s Foundation. Dr. Landier and Dr. Crowther reported no relevant conflicts of interest.

ORLANDO – Pill containers are not known for eloquence, but they tell a disturbing tale of patient over-reporting of adherence to essential leukemia maintenance therapy.

Among 416 children with acute lymphoblastic leukemia (ALL) in first remission, the number of days patients or their guardians reported that the child took his/her daily oral 6-mercaptopurine (6MP) for maintenance was significantly higher than the number of days the pill bottles were opened, as reported by an electronic medication management system.

“Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education,” said Dr. Wendy Landier from the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham.

The results suggest that patient self-reports of adherence to 6MP oral maintenance therapy may be unreliable, and should be taken with a grain of salt, Dr. Landier said in a briefing at the American Society of Hematology annual meeting.

The investigators had previously reported that poor adherence to oral 6MP maintenance therapy was associated with a nealy four-fold increased risk for relapse (JCO 30[17]:2094-101, Blood 124[15]:2345-53).

To better understand why some patients are poorly adherent to 6MP maintenance therapy, the investigator provided 416 children with ALL in first remission with pill containers equipped with a Medication Event Management System (MEMS) that electronically recorded the dates and times that each pill bottle was opened over a 16-week period. Patients age 12 and older or the parents/guardians of younger children were also asked to report the date and time of each daily oral dose at the end of each 28-day study month.

The authors collected and evaluated a total of 1344 patient-months of self-report and MEMS data, compared the records, and stratified patients as either “perfect reporters”, whose self-reports matched the objective MEMS data; “over-reporters”, who self-report exceeded the MEMS data on 5 or more days per month for more than half of study months, and “others.”The median patient age at study entry was 6 years (range 2 to 20 years).

The authors reported in their study that 40.4% of patients were not adherent to oral 6MP therapy, as evidence by a mismatch between self-report and objective (MEMS) reporting.

The overall adjusted mean number of self-reported days per month that patients took their pills ranged from a low of 25.8+5.3 to a high of 26.1+4.5. The pill bottles, however, told a different tale, reporting that they had been opened from a low of 22.8 ± 6.4 to a high of 25.4 ± 4.5 days per month.

Month-by-month correlations between self-report and MEMS 0.36 to 0.58, and were all statistically significant.

In logistic regression models adjusted for thiopurine methyltransferase (TMPT) genotype, 6MP dose intensity, and 6-thiogaunine levels in red cells, significant predictors for over-reporting included older age, with an odds ratio (OR) of 1.07 for every 1-year increase in age (P = .04); Hispanic origin (OR 2.4, P = .02); Asian origin, (OR 3.1 P = .02; African-American origin (OR 5.3, P < .001); paternal education level lower than college (OR 2.1, P = .02); and 6MP non-adherence (OR 8.6, P < .0001).

Dr. Landier noted that 78.6% of over-reporters were non-adherent, compared with only 2% of perfect reporters.

“The real importance of this paper from my perspective is this: there is a famous quote that if the patient doesn’t take the medication it can’t work and in an era where we’re trying to improve the care of patients, one of the things we oftentimes forget that if the medication isn’t being taken, the patient can’t get better from it,” said Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster University in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was supported by grants from the National Institutes of Health and from St. Baldrick’s Foundation. Dr. Landier and Dr. Crowther reported no relevant conflicts of interest.

ORLANDO – Pill containers are not known for eloquence, but they tell a disturbing tale of patient over-reporting of adherence to essential leukemia maintenance therapy.

Among 416 children with acute lymphoblastic leukemia (ALL) in first remission, the number of days patients or their guardians reported that the child took his/her daily oral 6-mercaptopurine (6MP) for maintenance was significantly higher than the number of days the pill bottles were opened, as reported by an electronic medication management system.

“Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education,” said Dr. Wendy Landier from the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham.

The results suggest that patient self-reports of adherence to 6MP oral maintenance therapy may be unreliable, and should be taken with a grain of salt, Dr. Landier said in a briefing at the American Society of Hematology annual meeting.

The investigators had previously reported that poor adherence to oral 6MP maintenance therapy was associated with a nealy four-fold increased risk for relapse (JCO 30[17]:2094-101, Blood 124[15]:2345-53).

To better understand why some patients are poorly adherent to 6MP maintenance therapy, the investigator provided 416 children with ALL in first remission with pill containers equipped with a Medication Event Management System (MEMS) that electronically recorded the dates and times that each pill bottle was opened over a 16-week period. Patients age 12 and older or the parents/guardians of younger children were also asked to report the date and time of each daily oral dose at the end of each 28-day study month.

The authors collected and evaluated a total of 1344 patient-months of self-report and MEMS data, compared the records, and stratified patients as either “perfect reporters”, whose self-reports matched the objective MEMS data; “over-reporters”, who self-report exceeded the MEMS data on 5 or more days per month for more than half of study months, and “others.”The median patient age at study entry was 6 years (range 2 to 20 years).

The authors reported in their study that 40.4% of patients were not adherent to oral 6MP therapy, as evidence by a mismatch between self-report and objective (MEMS) reporting.

The overall adjusted mean number of self-reported days per month that patients took their pills ranged from a low of 25.8+5.3 to a high of 26.1+4.5. The pill bottles, however, told a different tale, reporting that they had been opened from a low of 22.8 ± 6.4 to a high of 25.4 ± 4.5 days per month.

Month-by-month correlations between self-report and MEMS 0.36 to 0.58, and were all statistically significant.

In logistic regression models adjusted for thiopurine methyltransferase (TMPT) genotype, 6MP dose intensity, and 6-thiogaunine levels in red cells, significant predictors for over-reporting included older age, with an odds ratio (OR) of 1.07 for every 1-year increase in age (P = .04); Hispanic origin (OR 2.4, P = .02); Asian origin, (OR 3.1 P = .02; African-American origin (OR 5.3, P < .001); paternal education level lower than college (OR 2.1, P = .02); and 6MP non-adherence (OR 8.6, P < .0001).

Dr. Landier noted that 78.6% of over-reporters were non-adherent, compared with only 2% of perfect reporters.

“The real importance of this paper from my perspective is this: there is a famous quote that if the patient doesn’t take the medication it can’t work and in an era where we’re trying to improve the care of patients, one of the things we oftentimes forget that if the medication isn’t being taken, the patient can’t get better from it,” said Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster University in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was supported by grants from the National Institutes of Health and from St. Baldrick’s Foundation. Dr. Landier and Dr. Crowther reported no relevant conflicts of interest.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).

Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.

Mary Jo Dales

The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.

The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.

After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.

Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.

Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.

Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.

The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.

In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Dr. Raetz had no relevant financial disclosures.

Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).

[email protected]

On Twitter @maryjodales

ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).

Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.

Mary Jo Dales

The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.

The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.

After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.

Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.

Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.

Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.

The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.

In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Dr. Raetz had no relevant financial disclosures.

Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).

[email protected]

On Twitter @maryjodales

ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).

Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.

Mary Jo Dales

The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.

The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.

After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.

Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.

Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.

Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.

The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.

In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Dr. Raetz had no relevant financial disclosures.

Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).

[email protected]

On Twitter @maryjodales

ORLANDO – Stored red blood cells continue to do their primary job of tissue reoxygenation for more than a month after being collected, a finding that has profound positive implications for countries where blood products are in perennially short supply and demand is high, said investigators from Africa and North America.

In a randomized controlled clinical trial, red blood cells (RBCs) stored for 25 to 35 days were not-inferior to RBCs stored for 1 to 10 days for tissue reox-ygenation in African children with severe anemia with lactic acidosis.

“We found no justification to shorten the current storage duration for RBCs judged by their fundamental role to deliver oxygen,” said Dr. Christine M. Cserti-Gazdewich from the University of Toronto, Ontario, Canada.

Their findings suggest that stored RBCs should be evaluated by their ability to effectively deliver oxygen to tissues rather than by the cell survival measures and in vitro markers of hemolysis used as the current standard for viability by regulatory agencies, Dr. Cserti-Gazdewich said at the American Society of Hematology annual meeting.

The study clinicaltrials.gov ID NCT01586923 is also published online in JAMA.

“This study won’t change our clinical practice, but it will substantiate what we have been doing,” said co-author Dr. Walter H “Sunny” Dzik from Mas-sachusetts General Hospital in Boston, in an interview.

“We didn’t go into this business to harm people, yet there’s a lot of lab data that has been pointing fingers at us, suggesting rather forcefully that by try-ing to manage blood inventories using older blood that we’re harming people,” he said.

Concerns about the shelf life of RBCs derive from evidence that the cells undergo cumulative changes in structure, biochemistry, and enzymatic active that ultimately could degrade their ability to deliver oxygen to target tissues. But those studies were based largely on laboratory findings and not on clinical practice, she noted.

To see whether RBCs stored for up to 5 weeks could be as effective at tissue oxygenation as more recently packaged cells, the investigators conducted a randomized clinical trial at a university hospital urgent-care facility in Kampala, Uganda, where diseases such as malaria and sickle-cell anemia, as well as malnutrion, cause severe anemia on a scale seldom seen in the developed world.

They enrolled 290 children from the ages of 6 to 60 months who presented with lactic acidosis due to severe anemia in the absence of shock, trauma, impaired cardiac function, refractory hypoxia, liver disease, or tissue injury. The patients all had hemoglobin levels of 5 g/dL or5 less, and serum lactate levels of 5 mM or greater.

The patients were randomly assigned, 145 to each study arm, to receive leukoreduced RBCs stored for either 1-10 days or from 25 to 35 days. All patients received 10 mL/kg of RBCs over 2 hours at the start of the study and, if indicated per protocol, an additional 10 mL/kg during hours 4-6. Blood lactate levels were measured at baseline and at 2, 4, 6, 8 and 24 hours.

The mean hemoglobin level at presentation was 3.7 ±1.3 g/dL and mean lactate was 9.3 ±3.4 mM.

The investigators found that the proportion of patients achieving a lactate ≤ 3 mM at 8 hours was 58% among patients who received the short-storage RBCs, compared with 61% among patients who received long-storage cells (P = 0.72). This result met the primary endpoint of non-inferiority for long-er-stored RBCs.

In fact, there were no significant differences between the groups in mean lactate levels at any of the time points beyond baseline.

There were no significant differences in lactate clearance, and there were similar degrees of improvement in clinical assessments, serial measurements of hemoglobin concentration, cerebral tissue oxygen saturation, and electrolyte abnormalities following RBC transfusions.

Adverse events, 30-day recovery, and survival were also comparable between the groups.

The authors also found in a pre-specified sub-group analysis that there were no significant between group differences in those patients who received a total of 20 mL/kg RBCs, Dr. Cserti-Gazdewich said.

“This is a crushingly urgent problem, in that there have been belief systems developed over the last couple of years that older blood is not as good as newer blood, without any real evidence to support that. The evidence that Christine is [presenting], I think, is pretty compelling evidence that that hy-pothesis is incorrect,” commented Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster Univer-sity in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was funded by the National Institutes of Health. Dr. Cserti-Gazdewich, Dr. Dzik, and Dr. Crowther reported having no relevant conflicts of interest.

ORLANDO – Stored red blood cells continue to do their primary job of tissue reoxygenation for more than a month after being collected, a finding that has profound positive implications for countries where blood products are in perennially short supply and demand is high, said investigators from Africa and North America.

In a randomized controlled clinical trial, red blood cells (RBCs) stored for 25 to 35 days were not-inferior to RBCs stored for 1 to 10 days for tissue reox-ygenation in African children with severe anemia with lactic acidosis.

“We found no justification to shorten the current storage duration for RBCs judged by their fundamental role to deliver oxygen,” said Dr. Christine M. Cserti-Gazdewich from the University of Toronto, Ontario, Canada.

Their findings suggest that stored RBCs should be evaluated by their ability to effectively deliver oxygen to tissues rather than by the cell survival measures and in vitro markers of hemolysis used as the current standard for viability by regulatory agencies, Dr. Cserti-Gazdewich said at the American Society of Hematology annual meeting.

The study clinicaltrials.gov ID NCT01586923 is also published online in JAMA.

“This study won’t change our clinical practice, but it will substantiate what we have been doing,” said co-author Dr. Walter H “Sunny” Dzik from Mas-sachusetts General Hospital in Boston, in an interview.

“We didn’t go into this business to harm people, yet there’s a lot of lab data that has been pointing fingers at us, suggesting rather forcefully that by try-ing to manage blood inventories using older blood that we’re harming people,” he said.

Concerns about the shelf life of RBCs derive from evidence that the cells undergo cumulative changes in structure, biochemistry, and enzymatic active that ultimately could degrade their ability to deliver oxygen to target tissues. But those studies were based largely on laboratory findings and not on clinical practice, she noted.

To see whether RBCs stored for up to 5 weeks could be as effective at tissue oxygenation as more recently packaged cells, the investigators conducted a randomized clinical trial at a university hospital urgent-care facility in Kampala, Uganda, where diseases such as malaria and sickle-cell anemia, as well as malnutrion, cause severe anemia on a scale seldom seen in the developed world.

They enrolled 290 children from the ages of 6 to 60 months who presented with lactic acidosis due to severe anemia in the absence of shock, trauma, impaired cardiac function, refractory hypoxia, liver disease, or tissue injury. The patients all had hemoglobin levels of 5 g/dL or5 less, and serum lactate levels of 5 mM or greater.

The patients were randomly assigned, 145 to each study arm, to receive leukoreduced RBCs stored for either 1-10 days or from 25 to 35 days. All patients received 10 mL/kg of RBCs over 2 hours at the start of the study and, if indicated per protocol, an additional 10 mL/kg during hours 4-6. Blood lactate levels were measured at baseline and at 2, 4, 6, 8 and 24 hours.

The mean hemoglobin level at presentation was 3.7 ±1.3 g/dL and mean lactate was 9.3 ±3.4 mM.

The investigators found that the proportion of patients achieving a lactate ≤ 3 mM at 8 hours was 58% among patients who received the short-storage RBCs, compared with 61% among patients who received long-storage cells (P = 0.72). This result met the primary endpoint of non-inferiority for long-er-stored RBCs.

In fact, there were no significant differences between the groups in mean lactate levels at any of the time points beyond baseline.

There were no significant differences in lactate clearance, and there were similar degrees of improvement in clinical assessments, serial measurements of hemoglobin concentration, cerebral tissue oxygen saturation, and electrolyte abnormalities following RBC transfusions.

Adverse events, 30-day recovery, and survival were also comparable between the groups.

The authors also found in a pre-specified sub-group analysis that there were no significant between group differences in those patients who received a total of 20 mL/kg RBCs, Dr. Cserti-Gazdewich said.

“This is a crushingly urgent problem, in that there have been belief systems developed over the last couple of years that older blood is not as good as newer blood, without any real evidence to support that. The evidence that Christine is [presenting], I think, is pretty compelling evidence that that hy-pothesis is incorrect,” commented Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster Univer-sity in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was funded by the National Institutes of Health. Dr. Cserti-Gazdewich, Dr. Dzik, and Dr. Crowther reported having no relevant conflicts of interest.

ORLANDO – Stored red blood cells continue to do their primary job of tissue reoxygenation for more than a month after being collected, a finding that has profound positive implications for countries where blood products are in perennially short supply and demand is high, said investigators from Africa and North America.

In a randomized controlled clinical trial, red blood cells (RBCs) stored for 25 to 35 days were not-inferior to RBCs stored for 1 to 10 days for tissue reox-ygenation in African children with severe anemia with lactic acidosis.

“We found no justification to shorten the current storage duration for RBCs judged by their fundamental role to deliver oxygen,” said Dr. Christine M. Cserti-Gazdewich from the University of Toronto, Ontario, Canada.

Their findings suggest that stored RBCs should be evaluated by their ability to effectively deliver oxygen to tissues rather than by the cell survival measures and in vitro markers of hemolysis used as the current standard for viability by regulatory agencies, Dr. Cserti-Gazdewich said at the American Society of Hematology annual meeting.

The study clinicaltrials.gov ID NCT01586923 is also published online in JAMA.

“This study won’t change our clinical practice, but it will substantiate what we have been doing,” said co-author Dr. Walter H “Sunny” Dzik from Mas-sachusetts General Hospital in Boston, in an interview.

“We didn’t go into this business to harm people, yet there’s a lot of lab data that has been pointing fingers at us, suggesting rather forcefully that by try-ing to manage blood inventories using older blood that we’re harming people,” he said.

Concerns about the shelf life of RBCs derive from evidence that the cells undergo cumulative changes in structure, biochemistry, and enzymatic active that ultimately could degrade their ability to deliver oxygen to target tissues. But those studies were based largely on laboratory findings and not on clinical practice, she noted.

To see whether RBCs stored for up to 5 weeks could be as effective at tissue oxygenation as more recently packaged cells, the investigators conducted a randomized clinical trial at a university hospital urgent-care facility in Kampala, Uganda, where diseases such as malaria and sickle-cell anemia, as well as malnutrion, cause severe anemia on a scale seldom seen in the developed world.

They enrolled 290 children from the ages of 6 to 60 months who presented with lactic acidosis due to severe anemia in the absence of shock, trauma, impaired cardiac function, refractory hypoxia, liver disease, or tissue injury. The patients all had hemoglobin levels of 5 g/dL or5 less, and serum lactate levels of 5 mM or greater.

The patients were randomly assigned, 145 to each study arm, to receive leukoreduced RBCs stored for either 1-10 days or from 25 to 35 days. All patients received 10 mL/kg of RBCs over 2 hours at the start of the study and, if indicated per protocol, an additional 10 mL/kg during hours 4-6. Blood lactate levels were measured at baseline and at 2, 4, 6, 8 and 24 hours.

The mean hemoglobin level at presentation was 3.7 ±1.3 g/dL and mean lactate was 9.3 ±3.4 mM.

The investigators found that the proportion of patients achieving a lactate ≤ 3 mM at 8 hours was 58% among patients who received the short-storage RBCs, compared with 61% among patients who received long-storage cells (P = 0.72). This result met the primary endpoint of non-inferiority for long-er-stored RBCs.

In fact, there were no significant differences between the groups in mean lactate levels at any of the time points beyond baseline.

There were no significant differences in lactate clearance, and there were similar degrees of improvement in clinical assessments, serial measurements of hemoglobin concentration, cerebral tissue oxygen saturation, and electrolyte abnormalities following RBC transfusions.

Adverse events, 30-day recovery, and survival were also comparable between the groups.

The authors also found in a pre-specified sub-group analysis that there were no significant between group differences in those patients who received a total of 20 mL/kg RBCs, Dr. Cserti-Gazdewich said.

“This is a crushingly urgent problem, in that there have been belief systems developed over the last couple of years that older blood is not as good as newer blood, without any real evidence to support that. The evidence that Christine is [presenting], I think, is pretty compelling evidence that that hy-pothesis is incorrect,” commented Dr. Mark Crowther, Professor and Chair in the Department of Pathology and Molecular Medicine of McMaster Univer-sity in Hamilton, Ontario, Canada. Dr. Crowther moderated a briefing where Dr. Cserti-Gazdewich presented the data.

The study was funded by the National Institutes of Health. Dr. Cserti-Gazdewich, Dr. Dzik, and Dr. Crowther reported having no relevant conflicts of interest.

ORLANDO – – Gene therapy can help restore immune function to older children and young adults with X-linked severe combined immunodeficiency, a team of US investigators reports.

“This is the first demonstration of the use of gene therapy to salvage failed allogeneic hematopoietic stem cell transplants in older SCID-X1 patients,” said Dr. Suk See De Ravin from the Laboratory of Host Defenses at the National Institutes of Health in Bethesda, Maryland.

Although allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor can be curative, transplants using parental bone marrow or genetically modified autologous transplants without myeloconditiong restore T-cell-mediated immunity but not humoral immunity, Dr. De Ravin said at the American Society of Hematology annual meeting.

Frontline Medical News

Additionally, transplants in older children with SCID-X1 who have persistent immune system defects – despite having received a transplant from a haploidentical donor in infancy – leave the patients with serious medical problems, including the life-long need for immunoglobulin G (IgG) supplementation, recurrent and chronic infections, warts, malnutrition, growth failure, and progressive diseases of the gut and lung.

Previous attempts at using gene therapy to correct mutations in IL2RG, the cause of SCID-X1, used mouse retroviral vectors to insert normal IL2RG into autologous hematopoietic stem cells without chemotherapy conditioning. This treatment restored T-cell immunity, but not B-cell- or natural killer (NK)-cell immunity

Of even greater concern is the fact that among infants with SCID-X1 who received autologous stem cells transduced with murine gamma retrovirus carrying the common gamma chain, 25% developed vector-associated leukemia.

To overcome these problems, investigators in the current study used a lentiviral vector containing an insulator fragment from a chicken beta-globin gene. The insulator fragment allows expression of the gamma chain complementary DNA while protecting against up-regulation of neighboring oncogenes.

Dr. De Ravin reported data on five patients from the ages of 7 to 24 years who had worsening immune dysfunction and complex medical problems, including dependence on immunoglobulin G (IgG) supplementations. All of the patients had previously undergone one or more HSCT from haploidentical donors.

The patients were treated with granulocyte-colony stimulating factor and plerixafor to mobilize peripheral blood cells, and then underwent apheresis to isolate CD34 cells. The cells were transduced in vitro with a lentiviral vector, and reinfused into patients after conditioning with low-dose busulfan (6 mg/kg). The vector was developed by researchers at St Jude Children’s Hospital in Memphis, Tennessee.

At the most recent follow-up, the first two patients treated with the protocol had stable engraftment of gamma-chain expressing cells gene with enhanced expression of B, T, and NK cells, with the cells continuing to show improvements, Early data on the remaining four patients indicates a similar positive trend.

Chimerism studies of the patients’ T-cells showed that the host cells were continuing to increase their contribution, suggesting gradual replacement over time of the T-cell graft, Dr. De Ravin said.

In the second patient treated, an increase in NK cells corresponded with an improvement in chronic warts. In addition, the first two patients began to produce both IgG and antigen-specific responses to vaccination, clearance of chronic norovirus infections, and resolution of their protein-losing enteropathy.

“Gene therapy does not appear to reverse prior organ damage, supporting early intervention to improve immunity in these patients before such damage occurs,” Dr. De Ravin said.

The study was supported by the National Institutes of Health. The viral vector was developed at St. Jude Children’s Research Hospital in Memphis, Tennessee. The authors reported no relevant conflicts of interest.

ORLANDO – – Gene therapy can help restore immune function to older children and young adults with X-linked severe combined immunodeficiency, a team of US investigators reports.

“This is the first demonstration of the use of gene therapy to salvage failed allogeneic hematopoietic stem cell transplants in older SCID-X1 patients,” said Dr. Suk See De Ravin from the Laboratory of Host Defenses at the National Institutes of Health in Bethesda, Maryland.

Although allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor can be curative, transplants using parental bone marrow or genetically modified autologous transplants without myeloconditiong restore T-cell-mediated immunity but not humoral immunity, Dr. De Ravin said at the American Society of Hematology annual meeting.

Frontline Medical News

Additionally, transplants in older children with SCID-X1 who have persistent immune system defects – despite having received a transplant from a haploidentical donor in infancy – leave the patients with serious medical problems, including the life-long need for immunoglobulin G (IgG) supplementation, recurrent and chronic infections, warts, malnutrition, growth failure, and progressive diseases of the gut and lung.

Previous attempts at using gene therapy to correct mutations in IL2RG, the cause of SCID-X1, used mouse retroviral vectors to insert normal IL2RG into autologous hematopoietic stem cells without chemotherapy conditioning. This treatment restored T-cell immunity, but not B-cell- or natural killer (NK)-cell immunity

Of even greater concern is the fact that among infants with SCID-X1 who received autologous stem cells transduced with murine gamma retrovirus carrying the common gamma chain, 25% developed vector-associated leukemia.

To overcome these problems, investigators in the current study used a lentiviral vector containing an insulator fragment from a chicken beta-globin gene. The insulator fragment allows expression of the gamma chain complementary DNA while protecting against up-regulation of neighboring oncogenes.

Dr. De Ravin reported data on five patients from the ages of 7 to 24 years who had worsening immune dysfunction and complex medical problems, including dependence on immunoglobulin G (IgG) supplementations. All of the patients had previously undergone one or more HSCT from haploidentical donors.

The patients were treated with granulocyte-colony stimulating factor and plerixafor to mobilize peripheral blood cells, and then underwent apheresis to isolate CD34 cells. The cells were transduced in vitro with a lentiviral vector, and reinfused into patients after conditioning with low-dose busulfan (6 mg/kg). The vector was developed by researchers at St Jude Children’s Hospital in Memphis, Tennessee.

At the most recent follow-up, the first two patients treated with the protocol had stable engraftment of gamma-chain expressing cells gene with enhanced expression of B, T, and NK cells, with the cells continuing to show improvements, Early data on the remaining four patients indicates a similar positive trend.

Chimerism studies of the patients’ T-cells showed that the host cells were continuing to increase their contribution, suggesting gradual replacement over time of the T-cell graft, Dr. De Ravin said.

In the second patient treated, an increase in NK cells corresponded with an improvement in chronic warts. In addition, the first two patients began to produce both IgG and antigen-specific responses to vaccination, clearance of chronic norovirus infections, and resolution of their protein-losing enteropathy.

“Gene therapy does not appear to reverse prior organ damage, supporting early intervention to improve immunity in these patients before such damage occurs,” Dr. De Ravin said.

The study was supported by the National Institutes of Health. The viral vector was developed at St. Jude Children’s Research Hospital in Memphis, Tennessee. The authors reported no relevant conflicts of interest.

ORLANDO – – Gene therapy can help restore immune function to older children and young adults with X-linked severe combined immunodeficiency, a team of US investigators reports.

“This is the first demonstration of the use of gene therapy to salvage failed allogeneic hematopoietic stem cell transplants in older SCID-X1 patients,” said Dr. Suk See De Ravin from the Laboratory of Host Defenses at the National Institutes of Health in Bethesda, Maryland.

Although allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor can be curative, transplants using parental bone marrow or genetically modified autologous transplants without myeloconditiong restore T-cell-mediated immunity but not humoral immunity, Dr. De Ravin said at the American Society of Hematology annual meeting.

Frontline Medical News

Additionally, transplants in older children with SCID-X1 who have persistent immune system defects – despite having received a transplant from a haploidentical donor in infancy – leave the patients with serious medical problems, including the life-long need for immunoglobulin G (IgG) supplementation, recurrent and chronic infections, warts, malnutrition, growth failure, and progressive diseases of the gut and lung.

Previous attempts at using gene therapy to correct mutations in IL2RG, the cause of SCID-X1, used mouse retroviral vectors to insert normal IL2RG into autologous hematopoietic stem cells without chemotherapy conditioning. This treatment restored T-cell immunity, but not B-cell- or natural killer (NK)-cell immunity

Of even greater concern is the fact that among infants with SCID-X1 who received autologous stem cells transduced with murine gamma retrovirus carrying the common gamma chain, 25% developed vector-associated leukemia.

To overcome these problems, investigators in the current study used a lentiviral vector containing an insulator fragment from a chicken beta-globin gene. The insulator fragment allows expression of the gamma chain complementary DNA while protecting against up-regulation of neighboring oncogenes.

Dr. De Ravin reported data on five patients from the ages of 7 to 24 years who had worsening immune dysfunction and complex medical problems, including dependence on immunoglobulin G (IgG) supplementations. All of the patients had previously undergone one or more HSCT from haploidentical donors.

The patients were treated with granulocyte-colony stimulating factor and plerixafor to mobilize peripheral blood cells, and then underwent apheresis to isolate CD34 cells. The cells were transduced in vitro with a lentiviral vector, and reinfused into patients after conditioning with low-dose busulfan (6 mg/kg). The vector was developed by researchers at St Jude Children’s Hospital in Memphis, Tennessee.

At the most recent follow-up, the first two patients treated with the protocol had stable engraftment of gamma-chain expressing cells gene with enhanced expression of B, T, and NK cells, with the cells continuing to show improvements, Early data on the remaining four patients indicates a similar positive trend.

Chimerism studies of the patients’ T-cells showed that the host cells were continuing to increase their contribution, suggesting gradual replacement over time of the T-cell graft, Dr. De Ravin said.

In the second patient treated, an increase in NK cells corresponded with an improvement in chronic warts. In addition, the first two patients began to produce both IgG and antigen-specific responses to vaccination, clearance of chronic norovirus infections, and resolution of their protein-losing enteropathy.

“Gene therapy does not appear to reverse prior organ damage, supporting early intervention to improve immunity in these patients before such damage occurs,” Dr. De Ravin said.

The study was supported by the National Institutes of Health. The viral vector was developed at St. Jude Children’s Research Hospital in Memphis, Tennessee. The authors reported no relevant conflicts of interest.