ASH 2015

ORLANDO – Monotherapy with ibrutinib (Imbruvica) prolonged survival longer than did standard chemotherapy using chlorambucil (Leukeran) in the front-line treatment of older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the phase III RESONATE-2 study.

Co–drug developers Pharmacyclics and Janssen Biotech announced this summer that ibrutinib, an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, had achieved its primary and secondary endpoints.

Courtesy: Neil Osterweil

But the first full look at the data at the annual meeting of the American Society of Hematology showed ibrutinib reduced the risk of progression or death by 84% by independent review compared with chlorambucil, which has been a standard first-line therapy in older CLL patients.

The results were simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1509388).

With a median follow-up of 18.4 months, median progression-free survival (PFS) had not been reached with ibrutinib vs. 19 months with chlorambucil (hazard ratio, 0.16; P less than .001).

By investigator assessment, ibrutinib reduced the risk of progression by 91%, with an 18-month PFS rate of 94% vs. 45% with chlorambucil (HR, 0.09; P less than .001).

The PFS benefit with ibrutinib was consistent regardless of patient age, Rai stage, ECOG (Eastern Cooperative Oncology Group) status, bulky disease, and importantly, such high-risk markers as chromosome 11q deletion and unmutated immunoglobulin heavy chain variable (IGHV) mutation status, study author Dr. Alessandra Tedeschi, of Hospital Niguarda Cà Granda, Milan, , said at a press briefing highlighting the study (Ab. 485).

In addition, ibrutinib led to an 84% reduction in the risk of death compared with chlorambucil (HR, 0.16; P = .001). The 24-month overall survival rate was 98% with ibrutinib versus 85% with chlorambucil.

Single-agent ibrutinib was approved in 2014 for patients with CLL who had received at least one prior therapy and for all patients with the deleterious 17p deletion on the basis of the phase III RESONATE trial in relapsed or refractory CLL.

Three-year follow-up in the phase II PCYC-1102 study signaled a benefit with ibrutinib in treatment-naive CLL, showing an overall response rate of 84%, 30-month PFS of 96%, and overall survival rate of 97% in a subset of 31 patients at least 65 years old (Blood. 2015 Apr 16;125[16]:2497-506).

“The phase III RESONATE-2 trial confirms the efficacy of ibrutinib in treatment-naive CLL patients, leading to a 91% reduction in risk of progression and 84% reduction in risk of death when compared to chlorambucil,” Dr. Tedeschi said.

In all, 269 patients, median age of 73 years, were evenly randomized to once-daily ibrutinib 420 mg until progression or unacceptable toxicity or chlorambucil 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Patients with the deleterious 17p deletion were excluded, as single-agent chlorambucil is not effective in this population.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

“This is very important in this category of elderly patients, in whom bone marrow failure is the most common cause of morbidity,” Dr. Tedeschi said.

There were 3 deaths on the ibrutinib arm and 17 on the chlorambucil arm.

The majority of patients (87%) in this older population with frequent comorbidities was able to continue on oral, once-daily ibrutinib with a median of 1.5 years of follow-up, she said.

The most common adverse events on ibrutinib were grade one diarrhea, fatigue, cough, and nausea that did not result in treatment discontinuation. On the chlorambucil arm, fatigue nausea, vomiting, and cytopenias occurred more frequently than with ibrutinib.

Grade 3 maculopapular rash occurred in 3% with ibrutinib and 2% with chlorambucil, she said.

Ibrutinib was associated with higher and not insignificant rates of atrial fibrillation and major hemorrhage compared with chlorambucil, said Dr. Brian T. Hill of the Taussig Cancer Institute at the Cleveland Clinic, who was not involved in the study. In our interview, Dr. Hill also questions the relevance today of chlorambucil monotherapy as the comparator arm in RESONATE-2.

Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, sponsored the study. Dr. Tedeschi reported having nothing to disclose. Several coauthors reported relationships with Pharmacyclics and Janssen.

[email protected]

ORLANDO – Monotherapy with ibrutinib (Imbruvica) prolonged survival longer than did standard chemotherapy using chlorambucil (Leukeran) in the front-line treatment of older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the phase III RESONATE-2 study.

Co–drug developers Pharmacyclics and Janssen Biotech announced this summer that ibrutinib, an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, had achieved its primary and secondary endpoints.

Courtesy: Neil Osterweil

But the first full look at the data at the annual meeting of the American Society of Hematology showed ibrutinib reduced the risk of progression or death by 84% by independent review compared with chlorambucil, which has been a standard first-line therapy in older CLL patients.

The results were simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1509388).

With a median follow-up of 18.4 months, median progression-free survival (PFS) had not been reached with ibrutinib vs. 19 months with chlorambucil (hazard ratio, 0.16; P less than .001).

By investigator assessment, ibrutinib reduced the risk of progression by 91%, with an 18-month PFS rate of 94% vs. 45% with chlorambucil (HR, 0.09; P less than .001).

The PFS benefit with ibrutinib was consistent regardless of patient age, Rai stage, ECOG (Eastern Cooperative Oncology Group) status, bulky disease, and importantly, such high-risk markers as chromosome 11q deletion and unmutated immunoglobulin heavy chain variable (IGHV) mutation status, study author Dr. Alessandra Tedeschi, of Hospital Niguarda Cà Granda, Milan, , said at a press briefing highlighting the study (Ab. 485).

In addition, ibrutinib led to an 84% reduction in the risk of death compared with chlorambucil (HR, 0.16; P = .001). The 24-month overall survival rate was 98% with ibrutinib versus 85% with chlorambucil.

Single-agent ibrutinib was approved in 2014 for patients with CLL who had received at least one prior therapy and for all patients with the deleterious 17p deletion on the basis of the phase III RESONATE trial in relapsed or refractory CLL.

Three-year follow-up in the phase II PCYC-1102 study signaled a benefit with ibrutinib in treatment-naive CLL, showing an overall response rate of 84%, 30-month PFS of 96%, and overall survival rate of 97% in a subset of 31 patients at least 65 years old (Blood. 2015 Apr 16;125[16]:2497-506).

“The phase III RESONATE-2 trial confirms the efficacy of ibrutinib in treatment-naive CLL patients, leading to a 91% reduction in risk of progression and 84% reduction in risk of death when compared to chlorambucil,” Dr. Tedeschi said.

In all, 269 patients, median age of 73 years, were evenly randomized to once-daily ibrutinib 420 mg until progression or unacceptable toxicity or chlorambucil 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Patients with the deleterious 17p deletion were excluded, as single-agent chlorambucil is not effective in this population.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

“This is very important in this category of elderly patients, in whom bone marrow failure is the most common cause of morbidity,” Dr. Tedeschi said.

There were 3 deaths on the ibrutinib arm and 17 on the chlorambucil arm.

The majority of patients (87%) in this older population with frequent comorbidities was able to continue on oral, once-daily ibrutinib with a median of 1.5 years of follow-up, she said.

The most common adverse events on ibrutinib were grade one diarrhea, fatigue, cough, and nausea that did not result in treatment discontinuation. On the chlorambucil arm, fatigue nausea, vomiting, and cytopenias occurred more frequently than with ibrutinib.

Grade 3 maculopapular rash occurred in 3% with ibrutinib and 2% with chlorambucil, she said.

Ibrutinib was associated with higher and not insignificant rates of atrial fibrillation and major hemorrhage compared with chlorambucil, said Dr. Brian T. Hill of the Taussig Cancer Institute at the Cleveland Clinic, who was not involved in the study. In our interview, Dr. Hill also questions the relevance today of chlorambucil monotherapy as the comparator arm in RESONATE-2.

Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, sponsored the study. Dr. Tedeschi reported having nothing to disclose. Several coauthors reported relationships with Pharmacyclics and Janssen.

[email protected]

ORLANDO – Monotherapy with ibrutinib (Imbruvica) prolonged survival longer than did standard chemotherapy using chlorambucil (Leukeran) in the front-line treatment of older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the phase III RESONATE-2 study.

Co–drug developers Pharmacyclics and Janssen Biotech announced this summer that ibrutinib, an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, had achieved its primary and secondary endpoints.

Courtesy: Neil Osterweil

But the first full look at the data at the annual meeting of the American Society of Hematology showed ibrutinib reduced the risk of progression or death by 84% by independent review compared with chlorambucil, which has been a standard first-line therapy in older CLL patients.

The results were simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1509388).

With a median follow-up of 18.4 months, median progression-free survival (PFS) had not been reached with ibrutinib vs. 19 months with chlorambucil (hazard ratio, 0.16; P less than .001).

By investigator assessment, ibrutinib reduced the risk of progression by 91%, with an 18-month PFS rate of 94% vs. 45% with chlorambucil (HR, 0.09; P less than .001).

The PFS benefit with ibrutinib was consistent regardless of patient age, Rai stage, ECOG (Eastern Cooperative Oncology Group) status, bulky disease, and importantly, such high-risk markers as chromosome 11q deletion and unmutated immunoglobulin heavy chain variable (IGHV) mutation status, study author Dr. Alessandra Tedeschi, of Hospital Niguarda Cà Granda, Milan, , said at a press briefing highlighting the study (Ab. 485).

In addition, ibrutinib led to an 84% reduction in the risk of death compared with chlorambucil (HR, 0.16; P = .001). The 24-month overall survival rate was 98% with ibrutinib versus 85% with chlorambucil.

Single-agent ibrutinib was approved in 2014 for patients with CLL who had received at least one prior therapy and for all patients with the deleterious 17p deletion on the basis of the phase III RESONATE trial in relapsed or refractory CLL.

Three-year follow-up in the phase II PCYC-1102 study signaled a benefit with ibrutinib in treatment-naive CLL, showing an overall response rate of 84%, 30-month PFS of 96%, and overall survival rate of 97% in a subset of 31 patients at least 65 years old (Blood. 2015 Apr 16;125[16]:2497-506).

“The phase III RESONATE-2 trial confirms the efficacy of ibrutinib in treatment-naive CLL patients, leading to a 91% reduction in risk of progression and 84% reduction in risk of death when compared to chlorambucil,” Dr. Tedeschi said.

In all, 269 patients, median age of 73 years, were evenly randomized to once-daily ibrutinib 420 mg until progression or unacceptable toxicity or chlorambucil 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Patients with the deleterious 17p deletion were excluded, as single-agent chlorambucil is not effective in this population.

Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets.

“This is very important in this category of elderly patients, in whom bone marrow failure is the most common cause of morbidity,” Dr. Tedeschi said.

There were 3 deaths on the ibrutinib arm and 17 on the chlorambucil arm.

The majority of patients (87%) in this older population with frequent comorbidities was able to continue on oral, once-daily ibrutinib with a median of 1.5 years of follow-up, she said.

The most common adverse events on ibrutinib were grade one diarrhea, fatigue, cough, and nausea that did not result in treatment discontinuation. On the chlorambucil arm, fatigue nausea, vomiting, and cytopenias occurred more frequently than with ibrutinib.

Grade 3 maculopapular rash occurred in 3% with ibrutinib and 2% with chlorambucil, she said.

Ibrutinib was associated with higher and not insignificant rates of atrial fibrillation and major hemorrhage compared with chlorambucil, said Dr. Brian T. Hill of the Taussig Cancer Institute at the Cleveland Clinic, who was not involved in the study. In our interview, Dr. Hill also questions the relevance today of chlorambucil monotherapy as the comparator arm in RESONATE-2.

Pharmacyclics, which is jointly developing ibrutinib with Janssen Biotech, sponsored the study. Dr. Tedeschi reported having nothing to disclose. Several coauthors reported relationships with Pharmacyclics and Janssen.

[email protected]

ORLANDO – The oral multikinase inhibitor midostaurin improved overall survival by 23% when added to standard chemotherapy and given as maintenance therapy for 1 year in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML) in the global phase III CALGB 10603/RATIFY trial.

The results struck a chord at the annual meeting of the American Society of Hematology because the benefits of targeted therapy have so far eluded AML patients despite transforming the treatment of other blood cancers. Currently, there are no approved, targeted treatments for AML.

CALGB 10603/RATIFY is the first large, controlled trial to show an overall survival benefit in the roughly 30% of AML patients with a mutation in the FLT3 gene.

“This is exciting because we haven’t had a new treatment in AML for 30 years,” Dr. Robert Hromas of the University of Florida, Gainesville, said while moderating a press conference highlighting the plenary abstract.

The results were a decade in the making after midostaurin failed previously when used in all AML patients rather than the subset with the FLT3 mutation. But the persistence of researchers, the international collaboration, and funding in cancer research paid off, Dr. Hromas said.

Study author Dr. Richard M. Stone, chief of staff at Dana-Farber Cancer Institute in Boston, reviewed the results of CALGB 10603/RATIFY in an interview.

CALGB 10603/RATIFY was sponsored by the Cancer Therapy Evaluation Program. Dr. Stone reported financial relationships with several drug companies including Novartis, which provided the study drug and sponsored the trial outside North America. Dr. Hromas disclosed serving as an uncompensated advisory board member without equity for Cloud Pharmaceuticals.

[email protected]

ORLANDO – The oral multikinase inhibitor midostaurin improved overall survival by 23% when added to standard chemotherapy and given as maintenance therapy for 1 year in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML) in the global phase III CALGB 10603/RATIFY trial.

The results struck a chord at the annual meeting of the American Society of Hematology because the benefits of targeted therapy have so far eluded AML patients despite transforming the treatment of other blood cancers. Currently, there are no approved, targeted treatments for AML.

CALGB 10603/RATIFY is the first large, controlled trial to show an overall survival benefit in the roughly 30% of AML patients with a mutation in the FLT3 gene.

“This is exciting because we haven’t had a new treatment in AML for 30 years,” Dr. Robert Hromas of the University of Florida, Gainesville, said while moderating a press conference highlighting the plenary abstract.

The results were a decade in the making after midostaurin failed previously when used in all AML patients rather than the subset with the FLT3 mutation. But the persistence of researchers, the international collaboration, and funding in cancer research paid off, Dr. Hromas said.

Study author Dr. Richard M. Stone, chief of staff at Dana-Farber Cancer Institute in Boston, reviewed the results of CALGB 10603/RATIFY in an interview.

CALGB 10603/RATIFY was sponsored by the Cancer Therapy Evaluation Program. Dr. Stone reported financial relationships with several drug companies including Novartis, which provided the study drug and sponsored the trial outside North America. Dr. Hromas disclosed serving as an uncompensated advisory board member without equity for Cloud Pharmaceuticals.

[email protected]

ORLANDO – The oral multikinase inhibitor midostaurin improved overall survival by 23% when added to standard chemotherapy and given as maintenance therapy for 1 year in newly diagnosed patients with FLT3-mutated acute myeloid leukemia (AML) in the global phase III CALGB 10603/RATIFY trial.

The results struck a chord at the annual meeting of the American Society of Hematology because the benefits of targeted therapy have so far eluded AML patients despite transforming the treatment of other blood cancers. Currently, there are no approved, targeted treatments for AML.

CALGB 10603/RATIFY is the first large, controlled trial to show an overall survival benefit in the roughly 30% of AML patients with a mutation in the FLT3 gene.

“This is exciting because we haven’t had a new treatment in AML for 30 years,” Dr. Robert Hromas of the University of Florida, Gainesville, said while moderating a press conference highlighting the plenary abstract.

The results were a decade in the making after midostaurin failed previously when used in all AML patients rather than the subset with the FLT3 mutation. But the persistence of researchers, the international collaboration, and funding in cancer research paid off, Dr. Hromas said.

Study author Dr. Richard M. Stone, chief of staff at Dana-Farber Cancer Institute in Boston, reviewed the results of CALGB 10603/RATIFY in an interview.

CALGB 10603/RATIFY was sponsored by the Cancer Therapy Evaluation Program. Dr. Stone reported financial relationships with several drug companies including Novartis, which provided the study drug and sponsored the trial outside North America. Dr. Hromas disclosed serving as an uncompensated advisory board member without equity for Cloud Pharmaceuticals.

[email protected]

ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.  

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.  

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.  

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ORLANDO – For patients with severe sickle cell disease, stem cell transplants from an HLA identical sibling are associated with “excellent” 3-year overall and event-free survival, results of a retrospective analysis show.

Data on 1,000 hematopoietic stem cell transplants (HSCT) in children and adults with sickle-cell disease performed in 88 centers in 23 countries showed a 3-year event-free-survival (EFS) rate of 90%, and 3-year overall survival (OS) rate of 94%, reported Dr. Barbara Cappelli from the Eurocord International Registry in Paris, France.

“Early referral to transplant for patients with severe sickle-cell disease is warranted, as age is an independent predictor for both event-free survival and overall survival,” she said about the study at a briefing at the American Society of Hematology annual meeting.

Patients who received donor cord blood had the best 3-year OS, at 99%, compared with 94% for patients who received bone marrow grafts, and 80% for those who received peripheral blood stem cells (PBSC).

“Transplants from peripheral blood are not recommended, because the result that there is higher mortality with transplants with peripheral blood,” she said.

The findings provide further evidence that for patients with severe sickle-disease who have an HLA-identical sibling available as a donor, HSCT can be curative with good safety, commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Dr. Thompson was not involved in the study, but moderated a briefing where the data were presented.

International Registries

HSCT is the only therapy currently known to be curative for sickle-cell disease, but due to the risk for early and late complications it is generally reserved for patients with the most severe anemia or most disabling symptoms.

To evaluate the efficacy and safety of HSCT for sickle-cell disease, the investigators took a retrospective look at data from bone marrow transplant registries covering Europe, Brazil, the United States, and other reporting centers.

They searched for data on all patients with sickle-cell disease, children and adults, who received a transplant from an HLA identical sibling from 1986 through 2013.

The majority of patients (85%) were younger than 16, with the median age at HSCT of 9 years (range 1 to 54 years). Stroke was the most common indication for HSCT.

In all, 87% of patients received a myeloablative conditioning regimen based on busulfan combined with either cyclophosphamide or fludarabine. The remaining 13% of patients underwent a reduced-intensity conditioning regimen, primarily with fludarabine and cyclophosphamide.

In vivo T-cell depletion was performed in 70% of patients, either with anti-thymocyte globulin (630 patients) or with alemtumumab (76).

Prophylaxis for graft vs. host disease (GVHD) was predominantly cyclosporine as monotherapy or in combination with methotrexate.

A large majority of patients (84%) received bone marrow grafts, 7% got PBSCs, and 9% received umbilical cord blood.

By 60 days, the cumulative incidence of engraftment was 98%, with a median cumulative incidence of platelet engraftment of 25 days.

The cumulative incidence of acute GVHD (within 100 days of transplant) 14.3%, and the cumulative incidence of chronic GVHD (out to 3 years) was 13.3%

In all, 71 patients (7%) required autologous reconstitution, 45 because of late graft failure, 31 patients (3%) underwent a second transplant and 67 patients (7%) died. Of the patients who died, 6% had received bone marrow, 1% had received cord blood, and 21% had received PBSC.

As noted before, respective EFS and OS 3 years after transplant were 90% and 94%.

In multivariate analysis controlled for transplant and demographic characteristics, the authors found that younger age at transplant and use of bone marrow or cord blood were independently associated with better EFS and OS. In addition, 3-year overall survival was significantly better among patients who received transplants from the year 2000 on.

The risk for acute GVHD was significantly associated with increasing age, but none of the variables tested were associated with chronic GVHD.

Dr. Cappelli said that ways to improve outcomes include performing pre-or post-natal diagnosis in at-risk families, performing HLA typing of all family members at the time of diagnosis, and going to transplant as soon as the criteria for severe sickle-cell disease are met.

The study was supported by Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR. Dr. Cappelli and Dr. Johnson reported having no conflicts of interest.

ORLANDO – For patients with severe sickle cell disease, stem cell transplants from an HLA identical sibling are associated with “excellent” 3-year overall and event-free survival, results of a retrospective analysis show.

Data on 1,000 hematopoietic stem cell transplants (HSCT) in children and adults with sickle-cell disease performed in 88 centers in 23 countries showed a 3-year event-free-survival (EFS) rate of 90%, and 3-year overall survival (OS) rate of 94%, reported Dr. Barbara Cappelli from the Eurocord International Registry in Paris, France.

“Early referral to transplant for patients with severe sickle-cell disease is warranted, as age is an independent predictor for both event-free survival and overall survival,” she said about the study at a briefing at the American Society of Hematology annual meeting.

Patients who received donor cord blood had the best 3-year OS, at 99%, compared with 94% for patients who received bone marrow grafts, and 80% for those who received peripheral blood stem cells (PBSC).

“Transplants from peripheral blood are not recommended, because the result that there is higher mortality with transplants with peripheral blood,” she said.

The findings provide further evidence that for patients with severe sickle-disease who have an HLA-identical sibling available as a donor, HSCT can be curative with good safety, commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Dr. Thompson was not involved in the study, but moderated a briefing where the data were presented.

International Registries

HSCT is the only therapy currently known to be curative for sickle-cell disease, but due to the risk for early and late complications it is generally reserved for patients with the most severe anemia or most disabling symptoms.

To evaluate the efficacy and safety of HSCT for sickle-cell disease, the investigators took a retrospective look at data from bone marrow transplant registries covering Europe, Brazil, the United States, and other reporting centers.

They searched for data on all patients with sickle-cell disease, children and adults, who received a transplant from an HLA identical sibling from 1986 through 2013.

The majority of patients (85%) were younger than 16, with the median age at HSCT of 9 years (range 1 to 54 years). Stroke was the most common indication for HSCT.

In all, 87% of patients received a myeloablative conditioning regimen based on busulfan combined with either cyclophosphamide or fludarabine. The remaining 13% of patients underwent a reduced-intensity conditioning regimen, primarily with fludarabine and cyclophosphamide.

In vivo T-cell depletion was performed in 70% of patients, either with anti-thymocyte globulin (630 patients) or with alemtumumab (76).

Prophylaxis for graft vs. host disease (GVHD) was predominantly cyclosporine as monotherapy or in combination with methotrexate.

A large majority of patients (84%) received bone marrow grafts, 7% got PBSCs, and 9% received umbilical cord blood.

By 60 days, the cumulative incidence of engraftment was 98%, with a median cumulative incidence of platelet engraftment of 25 days.

The cumulative incidence of acute GVHD (within 100 days of transplant) 14.3%, and the cumulative incidence of chronic GVHD (out to 3 years) was 13.3%

In all, 71 patients (7%) required autologous reconstitution, 45 because of late graft failure, 31 patients (3%) underwent a second transplant and 67 patients (7%) died. Of the patients who died, 6% had received bone marrow, 1% had received cord blood, and 21% had received PBSC.

As noted before, respective EFS and OS 3 years after transplant were 90% and 94%.

In multivariate analysis controlled for transplant and demographic characteristics, the authors found that younger age at transplant and use of bone marrow or cord blood were independently associated with better EFS and OS. In addition, 3-year overall survival was significantly better among patients who received transplants from the year 2000 on.

The risk for acute GVHD was significantly associated with increasing age, but none of the variables tested were associated with chronic GVHD.

Dr. Cappelli said that ways to improve outcomes include performing pre-or post-natal diagnosis in at-risk families, performing HLA typing of all family members at the time of diagnosis, and going to transplant as soon as the criteria for severe sickle-cell disease are met.

The study was supported by Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR. Dr. Cappelli and Dr. Johnson reported having no conflicts of interest.

ORLANDO – For patients with severe sickle cell disease, stem cell transplants from an HLA identical sibling are associated with “excellent” 3-year overall and event-free survival, results of a retrospective analysis show.

Data on 1,000 hematopoietic stem cell transplants (HSCT) in children and adults with sickle-cell disease performed in 88 centers in 23 countries showed a 3-year event-free-survival (EFS) rate of 90%, and 3-year overall survival (OS) rate of 94%, reported Dr. Barbara Cappelli from the Eurocord International Registry in Paris, France.

“Early referral to transplant for patients with severe sickle-cell disease is warranted, as age is an independent predictor for both event-free survival and overall survival,” she said about the study at a briefing at the American Society of Hematology annual meeting.

Patients who received donor cord blood had the best 3-year OS, at 99%, compared with 94% for patients who received bone marrow grafts, and 80% for those who received peripheral blood stem cells (PBSC).

“Transplants from peripheral blood are not recommended, because the result that there is higher mortality with transplants with peripheral blood,” she said.

The findings provide further evidence that for patients with severe sickle-disease who have an HLA-identical sibling available as a donor, HSCT can be curative with good safety, commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Dr. Thompson was not involved in the study, but moderated a briefing where the data were presented.

International Registries

HSCT is the only therapy currently known to be curative for sickle-cell disease, but due to the risk for early and late complications it is generally reserved for patients with the most severe anemia or most disabling symptoms.

To evaluate the efficacy and safety of HSCT for sickle-cell disease, the investigators took a retrospective look at data from bone marrow transplant registries covering Europe, Brazil, the United States, and other reporting centers.

They searched for data on all patients with sickle-cell disease, children and adults, who received a transplant from an HLA identical sibling from 1986 through 2013.

The majority of patients (85%) were younger than 16, with the median age at HSCT of 9 years (range 1 to 54 years). Stroke was the most common indication for HSCT.

In all, 87% of patients received a myeloablative conditioning regimen based on busulfan combined with either cyclophosphamide or fludarabine. The remaining 13% of patients underwent a reduced-intensity conditioning regimen, primarily with fludarabine and cyclophosphamide.

In vivo T-cell depletion was performed in 70% of patients, either with anti-thymocyte globulin (630 patients) or with alemtumumab (76).

Prophylaxis for graft vs. host disease (GVHD) was predominantly cyclosporine as monotherapy or in combination with methotrexate.

A large majority of patients (84%) received bone marrow grafts, 7% got PBSCs, and 9% received umbilical cord blood.

By 60 days, the cumulative incidence of engraftment was 98%, with a median cumulative incidence of platelet engraftment of 25 days.

The cumulative incidence of acute GVHD (within 100 days of transplant) 14.3%, and the cumulative incidence of chronic GVHD (out to 3 years) was 13.3%

In all, 71 patients (7%) required autologous reconstitution, 45 because of late graft failure, 31 patients (3%) underwent a second transplant and 67 patients (7%) died. Of the patients who died, 6% had received bone marrow, 1% had received cord blood, and 21% had received PBSC.

As noted before, respective EFS and OS 3 years after transplant were 90% and 94%.

In multivariate analysis controlled for transplant and demographic characteristics, the authors found that younger age at transplant and use of bone marrow or cord blood were independently associated with better EFS and OS. In addition, 3-year overall survival was significantly better among patients who received transplants from the year 2000 on.

The risk for acute GVHD was significantly associated with increasing age, but none of the variables tested were associated with chronic GVHD.

Dr. Cappelli said that ways to improve outcomes include performing pre-or post-natal diagnosis in at-risk families, performing HLA typing of all family members at the time of diagnosis, and going to transplant as soon as the criteria for severe sickle-cell disease are met.

The study was supported by Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR. Dr. Cappelli and Dr. Johnson reported having no conflicts of interest.

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

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

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

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

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

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

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

[email protected]

On Twitter @maryjodales

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

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

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

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

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

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

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

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

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

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

[email protected]

On Twitter @maryjodales

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

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

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

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

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

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

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

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

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

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

[email protected]

On Twitter @maryjodales