Anemia

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).

Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.

The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.

The full approved indication for Nivestym is as follows:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
• To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
• To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
• For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
• For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

For more details on Nivestym, see the full prescribing information.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).

Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.

The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.

The full approved indication for Nivestym is as follows:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
• To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
• To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
• For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
• For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

For more details on Nivestym, see the full prescribing information.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).

Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.

The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.

The full approved indication for Nivestym is as follows:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
• To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
• To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
• For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
• For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

For more details on Nivestym, see the full prescribing information.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta⁰-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta⁰-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta⁰-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.

Image by Betty Pace

Results of a phase 3 trial showed that L-glutamine can reduce complications of sickle cell disease (SCD).

SCD patients who received pharmaceutical-grade L-glutamine (with or without hydroxyurea) had a reduction in sickle cell crises, hospitalizations, and acute chest syndrome (ACS) when compared to patients who received placebo (with or without hydroxyurea).

Gastrointestinal events and pain in the chest (noncardiac), back, and extremities were more frequent in L-glutamine recipients than controls.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, and his colleagues reported these results in NEJM. The research was sponsored by Emmaus Medical.

Dr Niihara noted that L-glutamine (Endari), which was approved by the US Food and Drug Administration last summer, is the first treatment approved to treat SCD in pediatric patients age 5 and older and the first SCD treatment approved for adults in nearly 20 years.

“Our hope in sharing the results [of the phase 3 trial] is to aid in increasing the awareness of sickle cell disease, a life-long hereditary blood disorder which commonly affects those of African descent, as well as those from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent,” Dr Niihara said.

He and his colleagues enrolled 230 patients on the trial. One hundred and fifty-two were randomized to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day), and 78 were randomized to placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks.

Baseline characteristics were similar between the treatment arms. Most patients had sickle cell anemia—89.5% (n=136) in the L-glutamine arm and 91% (n=71) in the placebo arm. Several patients had sickle B⁰ thalassemia—9.2% (n=14) and 9.0% (n=7), respectively. Two patients in the L-glutamine arm had B⁺ thalassemia, but 1 of these patients did not receive L-glutamine.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% (n=79) and 57.7% (n=45), respectively.

Most patients received concomitant hydroxyurea—66.4% (n=101) in the L-glutamine arm and 66.7% (n=52) in the placebo arm.

Efficacy

Patients in the L-glutamine arm had 25% fewer pain crises than patients in the placebo arm. The median number of crises was 3 and 4, respectively (P=0.005).

The median time to a first crisis was 84 days in the L-glutamine arm and 54 days in the placebo arm (P=0.02). The median time to a second crisis was 212 days and 133 days, respectively (P=0.03).

The median number of hospitalizations was 2 in the L-glutamine arm and 3 in the placebo arm, which is a difference of 33% (P=0.005). The median cumulative number of days in the hospital was 6.5 and 11, respectively (P=0.02).

The incidence of ACS was significantly lower in the L-glutamine arm, with 8.6% of patients in that group having at least 1 episode of ACS and 23.1% of the placebo group having at least 1 episode (P=0.003).

Safety

The rate of adverse events (AEs) was 98% in the L-glutamine arm and 100% in the placebo arm. The rate of serious AEs was 78.2% and 87.1%, respectively.

AEs with a higher incidence in the L-glutamine arm (at least 5%) are listed in the table below.

Image by Betty Pace

Results of a phase 3 trial showed that L-glutamine can reduce complications of sickle cell disease (SCD).

SCD patients who received pharmaceutical-grade L-glutamine (with or without hydroxyurea) had a reduction in sickle cell crises, hospitalizations, and acute chest syndrome (ACS) when compared to patients who received placebo (with or without hydroxyurea).

Gastrointestinal events and pain in the chest (noncardiac), back, and extremities were more frequent in L-glutamine recipients than controls.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, and his colleagues reported these results in NEJM. The research was sponsored by Emmaus Medical.

Dr Niihara noted that L-glutamine (Endari), which was approved by the US Food and Drug Administration last summer, is the first treatment approved to treat SCD in pediatric patients age 5 and older and the first SCD treatment approved for adults in nearly 20 years.

“Our hope in sharing the results [of the phase 3 trial] is to aid in increasing the awareness of sickle cell disease, a life-long hereditary blood disorder which commonly affects those of African descent, as well as those from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent,” Dr Niihara said.

He and his colleagues enrolled 230 patients on the trial. One hundred and fifty-two were randomized to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day), and 78 were randomized to placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks.

Baseline characteristics were similar between the treatment arms. Most patients had sickle cell anemia—89.5% (n=136) in the L-glutamine arm and 91% (n=71) in the placebo arm. Several patients had sickle B⁰ thalassemia—9.2% (n=14) and 9.0% (n=7), respectively. Two patients in the L-glutamine arm had B⁺ thalassemia, but 1 of these patients did not receive L-glutamine.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% (n=79) and 57.7% (n=45), respectively.

Most patients received concomitant hydroxyurea—66.4% (n=101) in the L-glutamine arm and 66.7% (n=52) in the placebo arm.

Efficacy

Patients in the L-glutamine arm had 25% fewer pain crises than patients in the placebo arm. The median number of crises was 3 and 4, respectively (P=0.005).

The median time to a first crisis was 84 days in the L-glutamine arm and 54 days in the placebo arm (P=0.02). The median time to a second crisis was 212 days and 133 days, respectively (P=0.03).

The median number of hospitalizations was 2 in the L-glutamine arm and 3 in the placebo arm, which is a difference of 33% (P=0.005). The median cumulative number of days in the hospital was 6.5 and 11, respectively (P=0.02).

The incidence of ACS was significantly lower in the L-glutamine arm, with 8.6% of patients in that group having at least 1 episode of ACS and 23.1% of the placebo group having at least 1 episode (P=0.003).

Safety

The rate of adverse events (AEs) was 98% in the L-glutamine arm and 100% in the placebo arm. The rate of serious AEs was 78.2% and 87.1%, respectively.

AEs with a higher incidence in the L-glutamine arm (at least 5%) are listed in the table below.

Image by Betty Pace

Results of a phase 3 trial showed that L-glutamine can reduce complications of sickle cell disease (SCD).

SCD patients who received pharmaceutical-grade L-glutamine (with or without hydroxyurea) had a reduction in sickle cell crises, hospitalizations, and acute chest syndrome (ACS) when compared to patients who received placebo (with or without hydroxyurea).

Gastrointestinal events and pain in the chest (noncardiac), back, and extremities were more frequent in L-glutamine recipients than controls.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, and his colleagues reported these results in NEJM. The research was sponsored by Emmaus Medical.

Dr Niihara noted that L-glutamine (Endari), which was approved by the US Food and Drug Administration last summer, is the first treatment approved to treat SCD in pediatric patients age 5 and older and the first SCD treatment approved for adults in nearly 20 years.

“Our hope in sharing the results [of the phase 3 trial] is to aid in increasing the awareness of sickle cell disease, a life-long hereditary blood disorder which commonly affects those of African descent, as well as those from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent,” Dr Niihara said.

He and his colleagues enrolled 230 patients on the trial. One hundred and fifty-two were randomized to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day), and 78 were randomized to placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks.

Baseline characteristics were similar between the treatment arms. Most patients had sickle cell anemia—89.5% (n=136) in the L-glutamine arm and 91% (n=71) in the placebo arm. Several patients had sickle B⁰ thalassemia—9.2% (n=14) and 9.0% (n=7), respectively. Two patients in the L-glutamine arm had B⁺ thalassemia, but 1 of these patients did not receive L-glutamine.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% (n=79) and 57.7% (n=45), respectively.

Most patients received concomitant hydroxyurea—66.4% (n=101) in the L-glutamine arm and 66.7% (n=52) in the placebo arm.

Efficacy

Patients in the L-glutamine arm had 25% fewer pain crises than patients in the placebo arm. The median number of crises was 3 and 4, respectively (P=0.005).

The median time to a first crisis was 84 days in the L-glutamine arm and 54 days in the placebo arm (P=0.02). The median time to a second crisis was 212 days and 133 days, respectively (P=0.03).

The median number of hospitalizations was 2 in the L-glutamine arm and 3 in the placebo arm, which is a difference of 33% (P=0.005). The median cumulative number of days in the hospital was 6.5 and 11, respectively (P=0.02).

The incidence of ACS was significantly lower in the L-glutamine arm, with 8.6% of patients in that group having at least 1 episode of ACS and 23.1% of the placebo group having at least 1 episode (P=0.003).

Safety

The rate of adverse events (AEs) was 98% in the L-glutamine arm and 100% in the placebo arm. The rate of serious AEs was 78.2% and 87.1%, respectively.

AEs with a higher incidence in the L-glutamine arm (at least 5%) are listed in the table below.

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.

Disclaimer

The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Hemedicus or Frontline Medical Communications. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.

Disclaimer

The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Hemedicus or Frontline Medical Communications. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.

Disclaimer

The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Hemedicus or Frontline Medical Communications. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.

CDC/Janice Haney Carr

[email protected]

WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.

CDC/Janice Haney Carr

[email protected]

WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.

CDC/Janice Haney Carr

[email protected]

Micrograph showing MDS

The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.

APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.

Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.

The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.

Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.

However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose  voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.

A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.

Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.

Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”

“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.

“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”

The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.

APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.

APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.

Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.

The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.

Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.

However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose  voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.

A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.

Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.

Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”

“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.

“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”

The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.

APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.

APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.

Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.

The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.

Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.

However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose  voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.

A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.

Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.

Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”

“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.

“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”

The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.

APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.

WASHINGTON – An investigational drug for sickle cell disease (SCD) boosted hemoglobin levels while reducing hospitalizations and transfusion needs by approximately two-thirds in a small cohort of severely affected patients.

Dr_Microbe/Thinkstock

Voxelotor was generally well tolerated at a 900-mg once-daily oral dose. One patient developed grade 2 diarrhea after increasing the dose to 1,500 mg, but symptoms resolved after returning to the 900-mg dose. Another patient had transient mild diarrhea on 900 mg of voxelotor; the symptoms resolved without changing or stopping the drug, Dr. Bronté said. There were no serious treatment-related adverse events.

Among this seriously ill population, two patients died after beginning voxelotor treatment, but both deaths were judged to be unrelated to the treatment. Dr. Bronté reported that the two deceased patients, one of whom was on voxelotor for 16 months and the other for 7 months, did experience reduced transfusion needs and reduced VOC-related hospitalizations while on the drug, experiences that were similar to the surviving members of the cohort.

“Voxelotor administered via compassionate use demonstrated large improvements in anemia and hemolysis, including in patients with lower baseline hemoglobin than studied in clinical trials to date,” Dr. Bronté said.

Taken together with clinical improvements and improved patient-focused outcomes among a severely affected population, “these data … support ongoing investigation in controlled clinical trials to confirm the benefits of voxelotor in a broad range of patients with SCD,” she said.

The study was supported by Global Blood Therapeutics, the manufacturer of voxelotor. Dr. Bronté reported having no other conflicts of interest.

[email protected]

WASHINGTON – An investigational drug for sickle cell disease (SCD) boosted hemoglobin levels while reducing hospitalizations and transfusion needs by approximately two-thirds in a small cohort of severely affected patients.

Dr_Microbe/Thinkstock

Voxelotor was generally well tolerated at a 900-mg once-daily oral dose. One patient developed grade 2 diarrhea after increasing the dose to 1,500 mg, but symptoms resolved after returning to the 900-mg dose. Another patient had transient mild diarrhea on 900 mg of voxelotor; the symptoms resolved without changing or stopping the drug, Dr. Bronté said. There were no serious treatment-related adverse events.

Among this seriously ill population, two patients died after beginning voxelotor treatment, but both deaths were judged to be unrelated to the treatment. Dr. Bronté reported that the two deceased patients, one of whom was on voxelotor for 16 months and the other for 7 months, did experience reduced transfusion needs and reduced VOC-related hospitalizations while on the drug, experiences that were similar to the surviving members of the cohort.

“Voxelotor administered via compassionate use demonstrated large improvements in anemia and hemolysis, including in patients with lower baseline hemoglobin than studied in clinical trials to date,” Dr. Bronté said.

Taken together with clinical improvements and improved patient-focused outcomes among a severely affected population, “these data … support ongoing investigation in controlled clinical trials to confirm the benefits of voxelotor in a broad range of patients with SCD,” she said.

The study was supported by Global Blood Therapeutics, the manufacturer of voxelotor. Dr. Bronté reported having no other conflicts of interest.

[email protected]

WASHINGTON – An investigational drug for sickle cell disease (SCD) boosted hemoglobin levels while reducing hospitalizations and transfusion needs by approximately two-thirds in a small cohort of severely affected patients.

Dr_Microbe/Thinkstock

Voxelotor was generally well tolerated at a 900-mg once-daily oral dose. One patient developed grade 2 diarrhea after increasing the dose to 1,500 mg, but symptoms resolved after returning to the 900-mg dose. Another patient had transient mild diarrhea on 900 mg of voxelotor; the symptoms resolved without changing or stopping the drug, Dr. Bronté said. There were no serious treatment-related adverse events.

Among this seriously ill population, two patients died after beginning voxelotor treatment, but both deaths were judged to be unrelated to the treatment. Dr. Bronté reported that the two deceased patients, one of whom was on voxelotor for 16 months and the other for 7 months, did experience reduced transfusion needs and reduced VOC-related hospitalizations while on the drug, experiences that were similar to the surviving members of the cohort.

“Voxelotor administered via compassionate use demonstrated large improvements in anemia and hemolysis, including in patients with lower baseline hemoglobin than studied in clinical trials to date,” Dr. Bronté said.

Taken together with clinical improvements and improved patient-focused outcomes among a severely affected population, “these data … support ongoing investigation in controlled clinical trials to confirm the benefits of voxelotor in a broad range of patients with SCD,” she said.

The study was supported by Global Blood Therapeutics, the manufacturer of voxelotor. Dr. Bronté reported having no other conflicts of interest.

[email protected]

Photo from EHA

STOCKHOLM—An ongoing phase 2 study suggests voxelotor (GBT440) can benefit adolescents with sickle cell disease (SCD).

In the HOPE-KIDS 1 study, voxelotor produced sustained improvements in hemoglobin levels and a reduction in clinical measures of hemolysis in a cohort of adolescents with SCD, most of whom were also receiving hydroxyurea (HU).

The most common adverse events (AEs) related to voxelotor were nausea, vomiting, headache, and rash.

These results were presented in a poster (abstract PF709) at the 23rd Congress of the European Hematology Association (EHA).

HOPE-KIDS 1 is sponsored by Global Blood Therapeutics, Inc.

In this study, researchers are evaluating voxelotor in SCD patients ages 6 to 17. In part A, researchers evaluated a 600 mg daily dose of voxelotor. In part B, they are testing voxelotor at daily doses of 900 mg and 1500 mg in patients ages 12 to 17.

At EHA, the researchers presented data on 25 patients who received voxelotor at 900 mg/day for 24 weeks in part B. Eighty-eight percent of the patients (n=22) were also taking HU.

The patients’ median age was 14 (range, 12-17), and 56% were male. Ninety-six percent (n=24) had the HbSS genotype.

Forty-eight percent of patients had 1 to 4 vaso-occlusive crises (VOCs) in the past year, 8% had more than 4 VOCs, and 44% had 0 VOCs.

At baseline, the median hemoglobin was 8.9 g/dL, the median fetal hemoglobin was 10.8 g/dL, and the median time-averaged mean of maximum velocity was 110 cm/s.

All 25 patients were dosed with voxelotor, and 22 completed 24 weeks of dosing. One patient withdrew consent, 1 was lost to follow-up, and 1 patient discontinued due to noncompliance.

Of the 22 patients who completed 24 weeks of voxelotor treatment, all but 3 were receiving concurrent HU.

Results

Voxelotor-related AEs occurring in at least 2 patients included nausea (12%, n=3), vomiting (8%, n=2), headache (8%, n=2), and rash (8%, n=2).

There was 1 case of grade 3 urticaria, which resolved and did not recur with continued dosing. There were no discontinuations of voxelotor due to AEs.

Patients experienced increased hemoglobin levels and improved clinical measures of hemolysis at 24 weeks, as evaluated by changes from baseline in hemoglobin, percent of reticulocytes, and percent of unconjugated bilirubin.

In all, 43% of patients (9/21) achieved a hemoglobin response (>1 g/dL) at 24 weeks. The median hemoglobin change from baseline was 0.7 g/dL, the median reduction in reticulocytes was 22.9%, and the median reduction in unconjugated bilirubin was 38.6%.

Sixty-two percent of patients (13/21) had a reduction in daily symptoms at 24 weeks, as assessed by total symptom scores (TSS). There was a 39% median reduction in TSS from baseline.

Fifty-five percent of patients (11/20) had a numerical decrease in transcranial doppler (TCD) flow at 24 weeks. Among hemoglobin responders (>1 g/dL), 88% (7/8) had a numerical decrease in TCD at 24 weeks.

“We continue to be encouraged by the results of the ongoing HOPE-KIDS 1 study, which are consistent with inhibition of HbS polymerization by voxelotor and support its ongoing clinical evaluation as a potential disease-modifying therapy for both adults and adolescents with SCD,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics.

“Results to date support our ongoing development of voxelotor in a broad range of patients, including in our phase 3 HOPE study, which is also evaluating voxelotor at doses of 900 mg and 1500 mg per day in adolescents and adults. We continue to expect to announce top-line clinical data from part A of the HOPE study by the end of this quarter.”

Photo from EHA

STOCKHOLM—An ongoing phase 2 study suggests voxelotor (GBT440) can benefit adolescents with sickle cell disease (SCD).

In the HOPE-KIDS 1 study, voxelotor produced sustained improvements in hemoglobin levels and a reduction in clinical measures of hemolysis in a cohort of adolescents with SCD, most of whom were also receiving hydroxyurea (HU).

The most common adverse events (AEs) related to voxelotor were nausea, vomiting, headache, and rash.

These results were presented in a poster (abstract PF709) at the 23rd Congress of the European Hematology Association (EHA).

HOPE-KIDS 1 is sponsored by Global Blood Therapeutics, Inc.

In this study, researchers are evaluating voxelotor in SCD patients ages 6 to 17. In part A, researchers evaluated a 600 mg daily dose of voxelotor. In part B, they are testing voxelotor at daily doses of 900 mg and 1500 mg in patients ages 12 to 17.

At EHA, the researchers presented data on 25 patients who received voxelotor at 900 mg/day for 24 weeks in part B. Eighty-eight percent of the patients (n=22) were also taking HU.

The patients’ median age was 14 (range, 12-17), and 56% were male. Ninety-six percent (n=24) had the HbSS genotype.

Forty-eight percent of patients had 1 to 4 vaso-occlusive crises (VOCs) in the past year, 8% had more than 4 VOCs, and 44% had 0 VOCs.

At baseline, the median hemoglobin was 8.9 g/dL, the median fetal hemoglobin was 10.8 g/dL, and the median time-averaged mean of maximum velocity was 110 cm/s.

All 25 patients were dosed with voxelotor, and 22 completed 24 weeks of dosing. One patient withdrew consent, 1 was lost to follow-up, and 1 patient discontinued due to noncompliance.

Of the 22 patients who completed 24 weeks of voxelotor treatment, all but 3 were receiving concurrent HU.

Results

Voxelotor-related AEs occurring in at least 2 patients included nausea (12%, n=3), vomiting (8%, n=2), headache (8%, n=2), and rash (8%, n=2).

There was 1 case of grade 3 urticaria, which resolved and did not recur with continued dosing. There were no discontinuations of voxelotor due to AEs.

Patients experienced increased hemoglobin levels and improved clinical measures of hemolysis at 24 weeks, as evaluated by changes from baseline in hemoglobin, percent of reticulocytes, and percent of unconjugated bilirubin.

In all, 43% of patients (9/21) achieved a hemoglobin response (>1 g/dL) at 24 weeks. The median hemoglobin change from baseline was 0.7 g/dL, the median reduction in reticulocytes was 22.9%, and the median reduction in unconjugated bilirubin was 38.6%.

Sixty-two percent of patients (13/21) had a reduction in daily symptoms at 24 weeks, as assessed by total symptom scores (TSS). There was a 39% median reduction in TSS from baseline.

Fifty-five percent of patients (11/20) had a numerical decrease in transcranial doppler (TCD) flow at 24 weeks. Among hemoglobin responders (>1 g/dL), 88% (7/8) had a numerical decrease in TCD at 24 weeks.

“We continue to be encouraged by the results of the ongoing HOPE-KIDS 1 study, which are consistent with inhibition of HbS polymerization by voxelotor and support its ongoing clinical evaluation as a potential disease-modifying therapy for both adults and adolescents with SCD,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics.

“Results to date support our ongoing development of voxelotor in a broad range of patients, including in our phase 3 HOPE study, which is also evaluating voxelotor at doses of 900 mg and 1500 mg per day in adolescents and adults. We continue to expect to announce top-line clinical data from part A of the HOPE study by the end of this quarter.”

Photo from EHA

STOCKHOLM—An ongoing phase 2 study suggests voxelotor (GBT440) can benefit adolescents with sickle cell disease (SCD).

In the HOPE-KIDS 1 study, voxelotor produced sustained improvements in hemoglobin levels and a reduction in clinical measures of hemolysis in a cohort of adolescents with SCD, most of whom were also receiving hydroxyurea (HU).

The most common adverse events (AEs) related to voxelotor were nausea, vomiting, headache, and rash.

These results were presented in a poster (abstract PF709) at the 23rd Congress of the European Hematology Association (EHA).

HOPE-KIDS 1 is sponsored by Global Blood Therapeutics, Inc.

In this study, researchers are evaluating voxelotor in SCD patients ages 6 to 17. In part A, researchers evaluated a 600 mg daily dose of voxelotor. In part B, they are testing voxelotor at daily doses of 900 mg and 1500 mg in patients ages 12 to 17.

At EHA, the researchers presented data on 25 patients who received voxelotor at 900 mg/day for 24 weeks in part B. Eighty-eight percent of the patients (n=22) were also taking HU.

The patients’ median age was 14 (range, 12-17), and 56% were male. Ninety-six percent (n=24) had the HbSS genotype.

Forty-eight percent of patients had 1 to 4 vaso-occlusive crises (VOCs) in the past year, 8% had more than 4 VOCs, and 44% had 0 VOCs.

At baseline, the median hemoglobin was 8.9 g/dL, the median fetal hemoglobin was 10.8 g/dL, and the median time-averaged mean of maximum velocity was 110 cm/s.

All 25 patients were dosed with voxelotor, and 22 completed 24 weeks of dosing. One patient withdrew consent, 1 was lost to follow-up, and 1 patient discontinued due to noncompliance.

Of the 22 patients who completed 24 weeks of voxelotor treatment, all but 3 were receiving concurrent HU.

Results

Voxelotor-related AEs occurring in at least 2 patients included nausea (12%, n=3), vomiting (8%, n=2), headache (8%, n=2), and rash (8%, n=2).

There was 1 case of grade 3 urticaria, which resolved and did not recur with continued dosing. There were no discontinuations of voxelotor due to AEs.

Patients experienced increased hemoglobin levels and improved clinical measures of hemolysis at 24 weeks, as evaluated by changes from baseline in hemoglobin, percent of reticulocytes, and percent of unconjugated bilirubin.

In all, 43% of patients (9/21) achieved a hemoglobin response (>1 g/dL) at 24 weeks. The median hemoglobin change from baseline was 0.7 g/dL, the median reduction in reticulocytes was 22.9%, and the median reduction in unconjugated bilirubin was 38.6%.

Sixty-two percent of patients (13/21) had a reduction in daily symptoms at 24 weeks, as assessed by total symptom scores (TSS). There was a 39% median reduction in TSS from baseline.

Fifty-five percent of patients (11/20) had a numerical decrease in transcranial doppler (TCD) flow at 24 weeks. Among hemoglobin responders (>1 g/dL), 88% (7/8) had a numerical decrease in TCD at 24 weeks.

“We continue to be encouraged by the results of the ongoing HOPE-KIDS 1 study, which are consistent with inhibition of HbS polymerization by voxelotor and support its ongoing clinical evaluation as a potential disease-modifying therapy for both adults and adolescents with SCD,” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics.

“Results to date support our ongoing development of voxelotor in a broad range of patients, including in our phase 3 HOPE study, which is also evaluating voxelotor at doses of 900 mg and 1500 mg per day in adolescents and adults. We continue to expect to announce top-line clinical data from part A of the HOPE study by the end of this quarter.”