Bleeding Disorders

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

Lusutrombopag, an oral thrombopoietin receptor agonist, was found to reduce the need for platelet transfusion in patients with chronic liver disease with a planned invasive procedure, according to results in an abstract of a phase III trial that will be presented as a latebreaker at the annual meeting of the American Association for the Study of Liver Disease in San Francisco.

The novel therapy, which upregulates platelet production, was “efficacious and well tolerated,” producing a reduced risk of overall adverse events, including bleeding events, according to Dr. Namiki Izumi, Musashino Red Cross Hospital, Tokyo.

©ToyToy/Wikimedia Commons/Public Domain

In this ongoing global phase III trial, called L-PLUS 2, 96 patients with chronic liver disease, a platelet count less than 50,000/microL, and a planned invasive procedure were randomized to receive a once-daily 3-mg tablet of lusutrombopag or a matching placebo for 7 days. The primary endpoint was the need for a preoperative platelet transfusion.

“The proportion of patients who required no preoperative platelet transfusion was significantly greater with lusutrombopag [29.2% vs. 12.5%; P less than .0001],” Dr. Izumi reported. The proportion of responders, defined by a platelet count greater than or equal to 50,000/microL and a greater than or equal to 20,000/microL-increase from baseline, was also significantly greater in the lusutrombopag arm (77.1% vs. 6.3%; P less than .0001).

In addition, the median time with a platelet count greater than or equal to 50,000/microL was 22.1 days in those who received lusutrombopag but no platelet transfusion versus 3.3 days in the placebo patients who did receive transfusion (P less than 0.0001).

Many adverse events occurred less frequently in the arm randomized to lusutrombopag. This included bleeding events (14.6% vs. 27.1%) and postoperative fever (39.6% vs. 56.3%). The rates of procedural hypertension (41.7% vs. 37.5%) and procedural pain (45.8% vs. 41.7%) were slightly greater in the group randomized to lusutrombopag, but elevations in liver enzymes, such as aspartate aminotransferase (22.9% vs. 31.3%) were somewhat lower.

“Protocol-required imaging revealed one thromboembolic event of the portal venous system in each study arm, neither of which was related to platelets,” according to Dr. Izumi, who reported that no patient discontinued therapy as a result of an adverse event.

Because of the frequency with which thrombocytopenia is observed in patients with chronic liver disease, platelet transfusion is considered a standard procedure when an invasive intervention is planned, according to Dr. Izumi. The data from this trial suggest that preoperative treatment with lusutrombopag may be an alternative.

Dr. Izumi reported financial relationships with Bayer, Daiichi Sankyo, Gilead, Merck, and Shionogi.

Lusutrombopag, an oral thrombopoietin receptor agonist, was found to reduce the need for platelet transfusion in patients with chronic liver disease with a planned invasive procedure, according to results in an abstract of a phase III trial that will be presented as a latebreaker at the annual meeting of the American Association for the Study of Liver Disease in San Francisco.

The novel therapy, which upregulates platelet production, was “efficacious and well tolerated,” producing a reduced risk of overall adverse events, including bleeding events, according to Dr. Namiki Izumi, Musashino Red Cross Hospital, Tokyo.

©ToyToy/Wikimedia Commons/Public Domain

In this ongoing global phase III trial, called L-PLUS 2, 96 patients with chronic liver disease, a platelet count less than 50,000/microL, and a planned invasive procedure were randomized to receive a once-daily 3-mg tablet of lusutrombopag or a matching placebo for 7 days. The primary endpoint was the need for a preoperative platelet transfusion.

“The proportion of patients who required no preoperative platelet transfusion was significantly greater with lusutrombopag [29.2% vs. 12.5%; P less than .0001],” Dr. Izumi reported. The proportion of responders, defined by a platelet count greater than or equal to 50,000/microL and a greater than or equal to 20,000/microL-increase from baseline, was also significantly greater in the lusutrombopag arm (77.1% vs. 6.3%; P less than .0001).

In addition, the median time with a platelet count greater than or equal to 50,000/microL was 22.1 days in those who received lusutrombopag but no platelet transfusion versus 3.3 days in the placebo patients who did receive transfusion (P less than 0.0001).

Many adverse events occurred less frequently in the arm randomized to lusutrombopag. This included bleeding events (14.6% vs. 27.1%) and postoperative fever (39.6% vs. 56.3%). The rates of procedural hypertension (41.7% vs. 37.5%) and procedural pain (45.8% vs. 41.7%) were slightly greater in the group randomized to lusutrombopag, but elevations in liver enzymes, such as aspartate aminotransferase (22.9% vs. 31.3%) were somewhat lower.

“Protocol-required imaging revealed one thromboembolic event of the portal venous system in each study arm, neither of which was related to platelets,” according to Dr. Izumi, who reported that no patient discontinued therapy as a result of an adverse event.

Because of the frequency with which thrombocytopenia is observed in patients with chronic liver disease, platelet transfusion is considered a standard procedure when an invasive intervention is planned, according to Dr. Izumi. The data from this trial suggest that preoperative treatment with lusutrombopag may be an alternative.

Dr. Izumi reported financial relationships with Bayer, Daiichi Sankyo, Gilead, Merck, and Shionogi.

Lusutrombopag, an oral thrombopoietin receptor agonist, was found to reduce the need for platelet transfusion in patients with chronic liver disease with a planned invasive procedure, according to results in an abstract of a phase III trial that will be presented as a latebreaker at the annual meeting of the American Association for the Study of Liver Disease in San Francisco.

The novel therapy, which upregulates platelet production, was “efficacious and well tolerated,” producing a reduced risk of overall adverse events, including bleeding events, according to Dr. Namiki Izumi, Musashino Red Cross Hospital, Tokyo.

©ToyToy/Wikimedia Commons/Public Domain

In this ongoing global phase III trial, called L-PLUS 2, 96 patients with chronic liver disease, a platelet count less than 50,000/microL, and a planned invasive procedure were randomized to receive a once-daily 3-mg tablet of lusutrombopag or a matching placebo for 7 days. The primary endpoint was the need for a preoperative platelet transfusion.

“The proportion of patients who required no preoperative platelet transfusion was significantly greater with lusutrombopag [29.2% vs. 12.5%; P less than .0001],” Dr. Izumi reported. The proportion of responders, defined by a platelet count greater than or equal to 50,000/microL and a greater than or equal to 20,000/microL-increase from baseline, was also significantly greater in the lusutrombopag arm (77.1% vs. 6.3%; P less than .0001).

In addition, the median time with a platelet count greater than or equal to 50,000/microL was 22.1 days in those who received lusutrombopag but no platelet transfusion versus 3.3 days in the placebo patients who did receive transfusion (P less than 0.0001).

Many adverse events occurred less frequently in the arm randomized to lusutrombopag. This included bleeding events (14.6% vs. 27.1%) and postoperative fever (39.6% vs. 56.3%). The rates of procedural hypertension (41.7% vs. 37.5%) and procedural pain (45.8% vs. 41.7%) were slightly greater in the group randomized to lusutrombopag, but elevations in liver enzymes, such as aspartate aminotransferase (22.9% vs. 31.3%) were somewhat lower.

“Protocol-required imaging revealed one thromboembolic event of the portal venous system in each study arm, neither of which was related to platelets,” according to Dr. Izumi, who reported that no patient discontinued therapy as a result of an adverse event.

Because of the frequency with which thrombocytopenia is observed in patients with chronic liver disease, platelet transfusion is considered a standard procedure when an invasive intervention is planned, according to Dr. Izumi. The data from this trial suggest that preoperative treatment with lusutrombopag may be an alternative.

Dr. Izumi reported financial relationships with Bayer, Daiichi Sankyo, Gilead, Merck, and Shionogi.

The U.S. Food and Drug Administration has provided its first approval of a coagulation factor replacement drug specifically for patients with hereditary Factor X deficiency who are aged 12 years or older, the FDA said in a written statement. Typically, patients with this inherited disorder are treated with plasma-derived prothrombin complex concentrates.

Coagadex, the new coagulation factor replacement drug, was effective at controlling bleeding episodes in individuals with moderate to severe hereditary Factor X deficiency, in a 16-patient study. Prior to being treated with the purified Factor X concentrate, the study’s participants had the following types of bleeding episodes: spontaneous; traumatic; or heavy menstrual.

Researchers also conducted a smaller study of the drug’s effectiveness on patients who were undergoing surgery. In this research project, Coagadex was successful at controlling blood loss during and after surgery, in those patients with mild hereditary Factor X deficiency.

“The approval of Coagadex is a significant advancement for patients who suffer from this rare but serious disease,” said Dr. Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research, in the release.

Bio Products Laboratory manufactured the new drug.

[email protected]

The U.S. Food and Drug Administration has provided its first approval of a coagulation factor replacement drug specifically for patients with hereditary Factor X deficiency who are aged 12 years or older, the FDA said in a written statement. Typically, patients with this inherited disorder are treated with plasma-derived prothrombin complex concentrates.

Coagadex, the new coagulation factor replacement drug, was effective at controlling bleeding episodes in individuals with moderate to severe hereditary Factor X deficiency, in a 16-patient study. Prior to being treated with the purified Factor X concentrate, the study’s participants had the following types of bleeding episodes: spontaneous; traumatic; or heavy menstrual.

Researchers also conducted a smaller study of the drug’s effectiveness on patients who were undergoing surgery. In this research project, Coagadex was successful at controlling blood loss during and after surgery, in those patients with mild hereditary Factor X deficiency.

“The approval of Coagadex is a significant advancement for patients who suffer from this rare but serious disease,” said Dr. Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research, in the release.

Bio Products Laboratory manufactured the new drug.

[email protected]

The U.S. Food and Drug Administration has provided its first approval of a coagulation factor replacement drug specifically for patients with hereditary Factor X deficiency who are aged 12 years or older, the FDA said in a written statement. Typically, patients with this inherited disorder are treated with plasma-derived prothrombin complex concentrates.

Coagadex, the new coagulation factor replacement drug, was effective at controlling bleeding episodes in individuals with moderate to severe hereditary Factor X deficiency, in a 16-patient study. Prior to being treated with the purified Factor X concentrate, the study’s participants had the following types of bleeding episodes: spontaneous; traumatic; or heavy menstrual.

Researchers also conducted a smaller study of the drug’s effectiveness on patients who were undergoing surgery. In this research project, Coagadex was successful at controlling blood loss during and after surgery, in those patients with mild hereditary Factor X deficiency.

“The approval of Coagadex is a significant advancement for patients who suffer from this rare but serious disease,” said Dr. Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research, in the release.

Bio Products Laboratory manufactured the new drug.

[email protected]

The Food and Drug Administration has extended its approval of Promacta (eltrombopag) to include pediatric patients with chronic immune thrombocytopenic purpura, the agency announced Aug. 24.

Approved in 2008 for adults with immune thrombocytopenic purpura (ITP), eltrombopag is now approved for the treatment of the rare blood disorder in patients aged 1 year and older. The drug may be used in children who have not responded to other ITP medications or spleen surgery, the FDA said in a statement.

Eltrombopag’s efficacy and safety in children aged 1-17 years was established in two placebo-controlled trials comprising 159 patients. Findings from the first trial found that over 7 weeks, 62% of patients given eltrombopag had improved platelet counts without rescue therapy between weeks 1 and 6, compared with 32% in the placebo group.

In the second trial, which lasted 13 weeks, 41% of patients taking eltrombopag experienced increased platelet counts for at least 6 out of 8 weeks between weeks 5 and 12, compared with 3% of patients in the placebo group, the FDA reported.

“In both trials, patients taking Promacta also had less need for other treatments to increase their platelet counts, such as corticosteroids or platelet transfusions,” the FDA said. “Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.”

Eltrombopag may be taken once daily in tablet form, or as a powder mixed with liquid for children aged 1-5 years. It should be used only in ITP patients with an increased risk of bleeding.

The most common side effects in children were infections of the upper respiratory tract or nose and throat, diarrhea, abdominal pain, rash, and increase in liver enzymes.

Promacta is manufactured by Novartis in East Hanover, N.J.

[email protected]

The Food and Drug Administration has extended its approval of Promacta (eltrombopag) to include pediatric patients with chronic immune thrombocytopenic purpura, the agency announced Aug. 24.

Approved in 2008 for adults with immune thrombocytopenic purpura (ITP), eltrombopag is now approved for the treatment of the rare blood disorder in patients aged 1 year and older. The drug may be used in children who have not responded to other ITP medications or spleen surgery, the FDA said in a statement.

Eltrombopag’s efficacy and safety in children aged 1-17 years was established in two placebo-controlled trials comprising 159 patients. Findings from the first trial found that over 7 weeks, 62% of patients given eltrombopag had improved platelet counts without rescue therapy between weeks 1 and 6, compared with 32% in the placebo group.

In the second trial, which lasted 13 weeks, 41% of patients taking eltrombopag experienced increased platelet counts for at least 6 out of 8 weeks between weeks 5 and 12, compared with 3% of patients in the placebo group, the FDA reported.

“In both trials, patients taking Promacta also had less need for other treatments to increase their platelet counts, such as corticosteroids or platelet transfusions,” the FDA said. “Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.”

Eltrombopag may be taken once daily in tablet form, or as a powder mixed with liquid for children aged 1-5 years. It should be used only in ITP patients with an increased risk of bleeding.

The most common side effects in children were infections of the upper respiratory tract or nose and throat, diarrhea, abdominal pain, rash, and increase in liver enzymes.

Promacta is manufactured by Novartis in East Hanover, N.J.

[email protected]

The Food and Drug Administration has extended its approval of Promacta (eltrombopag) to include pediatric patients with chronic immune thrombocytopenic purpura, the agency announced Aug. 24.

Approved in 2008 for adults with immune thrombocytopenic purpura (ITP), eltrombopag is now approved for the treatment of the rare blood disorder in patients aged 1 year and older. The drug may be used in children who have not responded to other ITP medications or spleen surgery, the FDA said in a statement.

Eltrombopag’s efficacy and safety in children aged 1-17 years was established in two placebo-controlled trials comprising 159 patients. Findings from the first trial found that over 7 weeks, 62% of patients given eltrombopag had improved platelet counts without rescue therapy between weeks 1 and 6, compared with 32% in the placebo group.

In the second trial, which lasted 13 weeks, 41% of patients taking eltrombopag experienced increased platelet counts for at least 6 out of 8 weeks between weeks 5 and 12, compared with 3% of patients in the placebo group, the FDA reported.

“In both trials, patients taking Promacta also had less need for other treatments to increase their platelet counts, such as corticosteroids or platelet transfusions,” the FDA said. “Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.”

Eltrombopag may be taken once daily in tablet form, or as a powder mixed with liquid for children aged 1-5 years. It should be used only in ITP patients with an increased risk of bleeding.

The most common side effects in children were infections of the upper respiratory tract or nose and throat, diarrhea, abdominal pain, rash, and increase in liver enzymes.

Promacta is manufactured by Novartis in East Hanover, N.J.

[email protected]

For patients with chronic primary immune thrombocytopenia, a three-drug regimen was associated with a high response rate and relapse-free survival, according to the results of a single-arm, phase IIb trial published online in Blood.

Twenty patients with primary immune thrombocytopenia (ITP) received an investigative triple therapy of oral dexamethasone 40 mg (days 1-4), oral cyclosporine 2.5-3.0 mg/kg daily (days 1-28), and intravenous rituximab 100 mg (day 7, 14, 21, and 28), and of this group, 12 patients responded. The median time to response was 7.4 days, and all patients maintained their response for at least 7 months, Dr. Philip Young-Ill Choi, of St. George Clinical School, University of New South Wales, Kogarah, Australia, and his colleagues reported (Blood 2015;126[4]:500-3).

Complete response was 30% at 6 months, and only two patients relapsed during a median follow-up period of 17.5 months (range, 7-47 months). Among patients who responded, relapse-free survival at 12 and 24 months was 92% and 76%, respectively (95% confidence intervals, 53%-98% and 30%-93%, respectively).

Peripheral T cells declined for all patients, irrespective of response, but responders had lower CD4+ T cells than did nonresponders for 6 months after treatment (median, 0.62 vs. 0.91 x 10⁹/L; P less than .0001). Peripheral CD19+ B cells became undetectable for all patients by day 28, but recovery was earlier for patients younger than 50 years (median, 6.5 months vs. not reached; P = .0105).

The regimen was generally well tolerated, without any deaths, treatment-related serious adverse events, serum sickness, interruptions, or delays caused by toxicity.

A major advantage of this regimen is its short duration of therapy, and yet 12 of 20 patients enjoyed a prolonged remission of 7 months or longer without needing further treatment. However, interpretation of the data was limited by the small sample size, the investigators noted.

“Although our study shows encouraging results, the incremental benefit of cyclosporine to rituximab and dexamethasone remains unresolved, and randomized controlled trials are required,” they wrote.

No funding source for the study was given. One author reported receiving speaker’s fees from Roche, and another is on the speakers bureau and receives research funding from GlaxoSmithKline and Amgen. The remaining authors declared no competing financial interests.

For patients with chronic primary immune thrombocytopenia, a three-drug regimen was associated with a high response rate and relapse-free survival, according to the results of a single-arm, phase IIb trial published online in Blood.

Twenty patients with primary immune thrombocytopenia (ITP) received an investigative triple therapy of oral dexamethasone 40 mg (days 1-4), oral cyclosporine 2.5-3.0 mg/kg daily (days 1-28), and intravenous rituximab 100 mg (day 7, 14, 21, and 28), and of this group, 12 patients responded. The median time to response was 7.4 days, and all patients maintained their response for at least 7 months, Dr. Philip Young-Ill Choi, of St. George Clinical School, University of New South Wales, Kogarah, Australia, and his colleagues reported (Blood 2015;126[4]:500-3).

Complete response was 30% at 6 months, and only two patients relapsed during a median follow-up period of 17.5 months (range, 7-47 months). Among patients who responded, relapse-free survival at 12 and 24 months was 92% and 76%, respectively (95% confidence intervals, 53%-98% and 30%-93%, respectively).

Peripheral T cells declined for all patients, irrespective of response, but responders had lower CD4+ T cells than did nonresponders for 6 months after treatment (median, 0.62 vs. 0.91 x 10⁹/L; P less than .0001). Peripheral CD19+ B cells became undetectable for all patients by day 28, but recovery was earlier for patients younger than 50 years (median, 6.5 months vs. not reached; P = .0105).

The regimen was generally well tolerated, without any deaths, treatment-related serious adverse events, serum sickness, interruptions, or delays caused by toxicity.

A major advantage of this regimen is its short duration of therapy, and yet 12 of 20 patients enjoyed a prolonged remission of 7 months or longer without needing further treatment. However, interpretation of the data was limited by the small sample size, the investigators noted.

“Although our study shows encouraging results, the incremental benefit of cyclosporine to rituximab and dexamethasone remains unresolved, and randomized controlled trials are required,” they wrote.

No funding source for the study was given. One author reported receiving speaker’s fees from Roche, and another is on the speakers bureau and receives research funding from GlaxoSmithKline and Amgen. The remaining authors declared no competing financial interests.

For patients with chronic primary immune thrombocytopenia, a three-drug regimen was associated with a high response rate and relapse-free survival, according to the results of a single-arm, phase IIb trial published online in Blood.

Twenty patients with primary immune thrombocytopenia (ITP) received an investigative triple therapy of oral dexamethasone 40 mg (days 1-4), oral cyclosporine 2.5-3.0 mg/kg daily (days 1-28), and intravenous rituximab 100 mg (day 7, 14, 21, and 28), and of this group, 12 patients responded. The median time to response was 7.4 days, and all patients maintained their response for at least 7 months, Dr. Philip Young-Ill Choi, of St. George Clinical School, University of New South Wales, Kogarah, Australia, and his colleagues reported (Blood 2015;126[4]:500-3).

Complete response was 30% at 6 months, and only two patients relapsed during a median follow-up period of 17.5 months (range, 7-47 months). Among patients who responded, relapse-free survival at 12 and 24 months was 92% and 76%, respectively (95% confidence intervals, 53%-98% and 30%-93%, respectively).

Peripheral T cells declined for all patients, irrespective of response, but responders had lower CD4+ T cells than did nonresponders for 6 months after treatment (median, 0.62 vs. 0.91 x 10⁹/L; P less than .0001). Peripheral CD19+ B cells became undetectable for all patients by day 28, but recovery was earlier for patients younger than 50 years (median, 6.5 months vs. not reached; P = .0105).

The regimen was generally well tolerated, without any deaths, treatment-related serious adverse events, serum sickness, interruptions, or delays caused by toxicity.

A major advantage of this regimen is its short duration of therapy, and yet 12 of 20 patients enjoyed a prolonged remission of 7 months or longer without needing further treatment. However, interpretation of the data was limited by the small sample size, the investigators noted.

“Although our study shows encouraging results, the incremental benefit of cyclosporine to rituximab and dexamethasone remains unresolved, and randomized controlled trials are required,” they wrote.

No funding source for the study was given. One author reported receiving speaker’s fees from Roche, and another is on the speakers bureau and receives research funding from GlaxoSmithKline and Amgen. The remaining authors declared no competing financial interests.

Treatment with the thrombopoietin receptor agonist eltrombopag led to a sustained platelet response in 40% of children and adolescents with chronic immune thrombocytopenia, compared with only 3% of the placebo group, according to a randomized multicenter trial published online in The Lancet.

Eltrombopag is approved in the United States for adults with chronic immune thrombocytopenia (CIT) who have not responded adequately to corticosteroids, immunoglobulins, or splenectomy, but few trials have assessed CIT therapies in children, said Dr. John Grainger of the Royal Manchester Children’s Hospital and the University of Manchester (England) and his associates.

Their multicenter, international study included 92 patients up to age 17 with CIT. During the 13-week double-blinded period of the study, patients received once-daily placebo or eltrombopag dosed at 0.89-1.2 mg/kg for patients aged 1-5 years and at 25-50 mg for patients aged 6-17 years. Dosing ranges were adjusted for ethnicity as well as body weight because east Asians have higher eltrombopag exposures and need lower starting doses, the investigators noted. After the double-blinded period, all patients entered 24 weeks of open-label treatment with eltrombopag (Lancet. 2015 Jul 29. doi: 10.1016/S0140-6736(15)61107-2.).

A total of 25 (40%) patients who received eltrombopag achieved platelet counts of at least 50 × 10⁹ per L for at least 6 of the last 8 weeks of the double-blinded period, compared with only one patient (3%) on placebo (odds ratio, 18; 95% confidence interval, 2.3-140.9; P = .0004), said the researchers. Based on the World Health Organization bleeding scale, the percentage of patients who experienced grade 1-4 bleeding events fell from 63% at the start of the open-label period to 24% at the end, and clinically significant (grade 2-4) bleeding events dropped from 20% to 6%. Seven of 87 patients were able to stop all other drugs they were taking for CIT without needing rescue therapy during open-label treatment, the researchers said.

Two patients stopped eltrombopag because of elevated liver aminotransferases. Rates of nasopharyngitis, rhinitis, upper respiratory tract infection, and cough were more common for eltrombopag than placebo, the investigators reported. However, serious adverse events were more common with placebo (14% vs. 8%), and there were no deaths, thrombotic events, or malignancies. Safety trends were similar during the double-blinded and open-label study periods, they added.

GlaxoSmithKline funded the study. Dr. Grainger reported receiving honoraria from GlaxoSmithKline, Amgen, and Baxter. Eleven coauthors reported financial conflicts of interest with GlaxoSmithKline and a number of other pharmaceutical companies.

Treatment with the thrombopoietin receptor agonist eltrombopag led to a sustained platelet response in 40% of children and adolescents with chronic immune thrombocytopenia, compared with only 3% of the placebo group, according to a randomized multicenter trial published online in The Lancet.

Eltrombopag is approved in the United States for adults with chronic immune thrombocytopenia (CIT) who have not responded adequately to corticosteroids, immunoglobulins, or splenectomy, but few trials have assessed CIT therapies in children, said Dr. John Grainger of the Royal Manchester Children’s Hospital and the University of Manchester (England) and his associates.

Their multicenter, international study included 92 patients up to age 17 with CIT. During the 13-week double-blinded period of the study, patients received once-daily placebo or eltrombopag dosed at 0.89-1.2 mg/kg for patients aged 1-5 years and at 25-50 mg for patients aged 6-17 years. Dosing ranges were adjusted for ethnicity as well as body weight because east Asians have higher eltrombopag exposures and need lower starting doses, the investigators noted. After the double-blinded period, all patients entered 24 weeks of open-label treatment with eltrombopag (Lancet. 2015 Jul 29. doi: 10.1016/S0140-6736(15)61107-2.).

A total of 25 (40%) patients who received eltrombopag achieved platelet counts of at least 50 × 10⁹ per L for at least 6 of the last 8 weeks of the double-blinded period, compared with only one patient (3%) on placebo (odds ratio, 18; 95% confidence interval, 2.3-140.9; P = .0004), said the researchers. Based on the World Health Organization bleeding scale, the percentage of patients who experienced grade 1-4 bleeding events fell from 63% at the start of the open-label period to 24% at the end, and clinically significant (grade 2-4) bleeding events dropped from 20% to 6%. Seven of 87 patients were able to stop all other drugs they were taking for CIT without needing rescue therapy during open-label treatment, the researchers said.

Two patients stopped eltrombopag because of elevated liver aminotransferases. Rates of nasopharyngitis, rhinitis, upper respiratory tract infection, and cough were more common for eltrombopag than placebo, the investigators reported. However, serious adverse events were more common with placebo (14% vs. 8%), and there were no deaths, thrombotic events, or malignancies. Safety trends were similar during the double-blinded and open-label study periods, they added.

GlaxoSmithKline funded the study. Dr. Grainger reported receiving honoraria from GlaxoSmithKline, Amgen, and Baxter. Eleven coauthors reported financial conflicts of interest with GlaxoSmithKline and a number of other pharmaceutical companies.

Treatment with the thrombopoietin receptor agonist eltrombopag led to a sustained platelet response in 40% of children and adolescents with chronic immune thrombocytopenia, compared with only 3% of the placebo group, according to a randomized multicenter trial published online in The Lancet.

Eltrombopag is approved in the United States for adults with chronic immune thrombocytopenia (CIT) who have not responded adequately to corticosteroids, immunoglobulins, or splenectomy, but few trials have assessed CIT therapies in children, said Dr. John Grainger of the Royal Manchester Children’s Hospital and the University of Manchester (England) and his associates.

Their multicenter, international study included 92 patients up to age 17 with CIT. During the 13-week double-blinded period of the study, patients received once-daily placebo or eltrombopag dosed at 0.89-1.2 mg/kg for patients aged 1-5 years and at 25-50 mg for patients aged 6-17 years. Dosing ranges were adjusted for ethnicity as well as body weight because east Asians have higher eltrombopag exposures and need lower starting doses, the investigators noted. After the double-blinded period, all patients entered 24 weeks of open-label treatment with eltrombopag (Lancet. 2015 Jul 29. doi: 10.1016/S0140-6736(15)61107-2.).

A total of 25 (40%) patients who received eltrombopag achieved platelet counts of at least 50 × 10⁹ per L for at least 6 of the last 8 weeks of the double-blinded period, compared with only one patient (3%) on placebo (odds ratio, 18; 95% confidence interval, 2.3-140.9; P = .0004), said the researchers. Based on the World Health Organization bleeding scale, the percentage of patients who experienced grade 1-4 bleeding events fell from 63% at the start of the open-label period to 24% at the end, and clinically significant (grade 2-4) bleeding events dropped from 20% to 6%. Seven of 87 patients were able to stop all other drugs they were taking for CIT without needing rescue therapy during open-label treatment, the researchers said.

Two patients stopped eltrombopag because of elevated liver aminotransferases. Rates of nasopharyngitis, rhinitis, upper respiratory tract infection, and cough were more common for eltrombopag than placebo, the investigators reported. However, serious adverse events were more common with placebo (14% vs. 8%), and there were no deaths, thrombotic events, or malignancies. Safety trends were similar during the double-blinded and open-label study periods, they added.

GlaxoSmithKline funded the study. Dr. Grainger reported receiving honoraria from GlaxoSmithKline, Amgen, and Baxter. Eleven coauthors reported financial conflicts of interest with GlaxoSmithKline and a number of other pharmaceutical companies.

The antibiotic dicloxacillin appears to markedly decrease INR levels in patients taking warfarin, reducing the mean INR to subtherapeutic ranges in the majority who take both drugs concomitantly, according to a research letter to the editor published online July 20 in JAMA.

Adverse interactions between warfarin and other drugs are often suspected, but solid data are lacking. Case reports have suggested that the commonly used antibiotic dicloxacillin reduces warfarin’s anticoagulant effects, but no studies have examined the issue, said Anton Pottegård, Ph.D., of the department of clinical pharmacology, University of Southern Denmark, Odense, and his associates (JAMA 2015;314:296-7).

To further investigate that possibility, the investigators analyzed information in an anticoagulant database covering 7,400 patients treated by three outpatient clinics and 50 general practitioners during a 15-year period. They focused on weekly INR levels recorded for 236 patients (median age, 68 years), most of whom took warfarin because of atrial fibrillation or heart valve replacement.

The mean INR level before dicloxacillin exposure was 2.59, compared with 1.97 after dicloxacillin exposure (P < .001). A total of 144 patients (61%) had subtherapeutic INR levels (< 2.0) during the 2-4 weeks following a course of dicloxacillin, Dr. Pottegård and his associates said.

A similar but less drastic decrease was observed among the 64 patients taking a different anticoagulant, phenprocoumon, who were given dicloxacillin. Mean INR levels dropped from 2.61 before exposure to 2.30 afterward (P = .003), and 41% of the group had subtherapeutic INR levels after taking the antibiotic.

No sponsor was reported for this study. Dr. Pottegård and his associates reported having no relevant financial disclosures.

The antibiotic dicloxacillin appears to markedly decrease INR levels in patients taking warfarin, reducing the mean INR to subtherapeutic ranges in the majority who take both drugs concomitantly, according to a research letter to the editor published online July 20 in JAMA.

Adverse interactions between warfarin and other drugs are often suspected, but solid data are lacking. Case reports have suggested that the commonly used antibiotic dicloxacillin reduces warfarin’s anticoagulant effects, but no studies have examined the issue, said Anton Pottegård, Ph.D., of the department of clinical pharmacology, University of Southern Denmark, Odense, and his associates (JAMA 2015;314:296-7).

To further investigate that possibility, the investigators analyzed information in an anticoagulant database covering 7,400 patients treated by three outpatient clinics and 50 general practitioners during a 15-year period. They focused on weekly INR levels recorded for 236 patients (median age, 68 years), most of whom took warfarin because of atrial fibrillation or heart valve replacement.

The mean INR level before dicloxacillin exposure was 2.59, compared with 1.97 after dicloxacillin exposure (P < .001). A total of 144 patients (61%) had subtherapeutic INR levels (< 2.0) during the 2-4 weeks following a course of dicloxacillin, Dr. Pottegård and his associates said.

A similar but less drastic decrease was observed among the 64 patients taking a different anticoagulant, phenprocoumon, who were given dicloxacillin. Mean INR levels dropped from 2.61 before exposure to 2.30 afterward (P = .003), and 41% of the group had subtherapeutic INR levels after taking the antibiotic.

No sponsor was reported for this study. Dr. Pottegård and his associates reported having no relevant financial disclosures.

The antibiotic dicloxacillin appears to markedly decrease INR levels in patients taking warfarin, reducing the mean INR to subtherapeutic ranges in the majority who take both drugs concomitantly, according to a research letter to the editor published online July 20 in JAMA.

Adverse interactions between warfarin and other drugs are often suspected, but solid data are lacking. Case reports have suggested that the commonly used antibiotic dicloxacillin reduces warfarin’s anticoagulant effects, but no studies have examined the issue, said Anton Pottegård, Ph.D., of the department of clinical pharmacology, University of Southern Denmark, Odense, and his associates (JAMA 2015;314:296-7).

To further investigate that possibility, the investigators analyzed information in an anticoagulant database covering 7,400 patients treated by three outpatient clinics and 50 general practitioners during a 15-year period. They focused on weekly INR levels recorded for 236 patients (median age, 68 years), most of whom took warfarin because of atrial fibrillation or heart valve replacement.

The mean INR level before dicloxacillin exposure was 2.59, compared with 1.97 after dicloxacillin exposure (P < .001). A total of 144 patients (61%) had subtherapeutic INR levels (< 2.0) during the 2-4 weeks following a course of dicloxacillin, Dr. Pottegård and his associates said.

A similar but less drastic decrease was observed among the 64 patients taking a different anticoagulant, phenprocoumon, who were given dicloxacillin. Mean INR levels dropped from 2.61 before exposure to 2.30 afterward (P = .003), and 41% of the group had subtherapeutic INR levels after taking the antibiotic.

No sponsor was reported for this study. Dr. Pottegård and his associates reported having no relevant financial disclosures.