Anemia

Danielle Townsley, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators are pursuing an upfront approval for eltrombopag in combination with immunosuppressive therapy for the treatment of severe aplastic anemia (SAA).

Based on eltrombopag’s single-agent activity in refractory SAA, they hypothesized that its addition to standard immunosuppressive therapy of horse antithymocyte globulin (hATG) and cyclosporine (CsA) in the first-line setting could improve patient outcome.

And, in a phase 2 trial, it did.

“The addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” said Danielle

Townsley, MD, who presented the data at the 2015 ASH Annual Meeting.

Dr Townsley, of the National Heart, Lung, and Blood Institute, National Institutes of Health, in Bethesda, Maryland, presented the findings as abstract LBA-2.*

The US Food and Drug Administration approved eltrombopag to treat refractory SAA in November 2014, and the European Commission approved it in 2015.

Investigators believed eltrombopag in the upfront, treatment-naïve setting could yield higher overall response rates (ORRs) than the 60% to 70% achieved with standard immunosuppressives worldwide.

“[It was] logical to consider treating patients early at the start of their disease,” Dr Townsley said.

So she and her colleagues conducted an investigator-initiated, phase 2, single-center trial of eltrombopag combined with immunosuppressive agents for first-line treatment of SAA.

Study design and patient population

Patients had to have confirmed treatment-naïve SAA, be a minimum of 2 years old, and weigh more than 12 kg. They were excluded if they had prior immunosuppressive therapy with ATG, alemtuzumab, or cyclophosphamide. They were also excluded if they had liver cirrhosis, AST/ALT more than 5 times normal, or Fanconi anemia.

Primary endpoints of the study were complete response (CR) at 6 months and toxicity. Secondary endpoints included ORR and partial response (PR) rate, survival, clonal evolution, and relapse.

Investigators defined CR as having an absolute neutrophil count (ANC) of 1000/μL or higher, a hemoglobin level of 10 g/dL or higher, and a platelet count of 100,000/μL or higher. They defined PR as blood counts no longer meeting criteria for SAA or CR.

All 92 patients received standard hATG (on days 1 to 4) and CsA (for 6 months). Patients in cohort 1 (n=30) also received eltrombopag at 150 mg daily, starting on day 14 for 6 months.

Patients in cohort 2 (n=31) received eltrombopag at 150 mg daily, starting on day 14 for 3 months. And the 31 patients in cohort 3 started 150 mg of daily eltrombopag simultaneously with the immunosuppressants and continued to receive the drug for 6 months.

Investigators assessed response at 3 and 6 months and planned to follow patients for at least 5 years.

Patients in all cohorts were a median of 32 years (range, 3–82), with 21% being younger than 18. About half were male, 66% had less than 1% of a paroxysmal nocturnal hemoglobinuria clone, 37% had a median neutrophil count less than 200/μL, a median reticulocyte count of 20,000/μL (range, 1600–60,400/μL), and a median platelet count of 9000/μL (range, 0–37,000/μL).

Results

At 3 months, the ORR for the entire population was 81%, and the CR rate was 28%. The ORR was 77% in cohorts 1 and 2 and 92% in cohort 3. The CR rate was 17%, 26%, and 44% in cohorts 1, 2, and 3, respectively.

At 6 months, the ORR for the entire population was 86%, and the CR rate was 37%. The ORR was 80%, 87%, and 95% in cohorts 1, 2, and 3, respectively. And the CR rate was 33%, 26%, and 60%, respectively.

Compared to historic rates for patients on hATG and CsA alone, “the addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” Dr Townsley said.

“And for cohort 3, when eltrombopag is given on day 1, the rate of response in evaluable patients to date appears even higher, with 95% overall response rate at 6 months, of which 60% are complete.”

Dr Townsley also noted that, compared to historical experience, neutrophil recovery was more robust in responding patients treated with eltrombopag. Patients on eltrombopag had a mean ANC of 2253/μL, compared with an ANC of 1716/μL for the historic comparator.

“And likewise, more robust platelet recovery was observed with eltrombopag,” Dr Townsley said, with the eltrombopag-treated patients achieving a mean count of 115,262/μL, compared to a mean of 84,303/μL for the historic group.

She added that, among all eltrombopag-treated patients, the median time to neutrophil recovery was 29 days for an ANC greater than 200/μL and 47 days for an ANC greater than 500/μL. In cohort 3—in which eltrombopag was initiated on day 1—those endpoints were achieved in a median of 8 days and 38 days, respectively.

Patients became transfusion-independent for red cells in a median of 42 days and for platelets in a median of 32 days.

Eltrombopag-treated patients had a 99% overall survival at a median follow-up of 18 months (range 1 – 42) when censored for stem cell transplant. When not censored for transplant, their overall survival was 97%.

Adverse events

“The addition of eltrombopag to ATG and cyclosporine was, overall, well tolerated,” Dr Townsley said. “Few grade 3 to 4 events were attributed to eltrombopag.”

Severe cutaneous reactions in 2 patients caused eltrombopag to be stopped, and 10% of patients had grade 2–3 transaminase and bilirubin elevations.

Bone marrow biopsies revealed no increased fibrosis.

One patient with thymoma died while on study due to encephalopathy. And 2 deaths occurred after hematopoietic stem cell transplant, one with relapsed acute myeloid leukemia and the other from relapsed aplastic anemia.

Clonal evolution occurred in 7 patients, 2 who had achieved CR and evolved in 3 and 30 months. Neither patient had bone marrow dysplasia. One patient’s cytogenetics normalized, and the other had stable disease.

“In our protocol, we define any new cytogenetic abnormality as clonal evolution—we have always done this,” Dr Townsley said.

Of the other 5 patients who evolved, 1 achieved a CR and relapsed, 1 achieved a PR and relapsed, 2 achieved a PR, and 1 had no response. Three of these patients had stem cell transplants, 1 had stable disease, and 1 died of acute myeloid leukemia after stem cell transplant.

The investigators concluded that eltrombopag increases complete and overall hematologic response rates in treatment-naïve SAA patients. Immediate introduction of eltrombopag with immunosuppressant therapy may be optimal, and CR does not appear to prevent clonal evolution.

Investigators are currently in the process of conducting a long-term, serial genomic analysis. The study is open for accrual to an extension cohort.

Eltrombopag is marketed as Promacta in the US and Revolade in most countries outside the US.

Dr Townsley disclosed drug and research funding from GlaxoSmithKline and Novartis, developers of eltrombopag.

*Data in the abstract differ from the presentation.

Danielle Townsley, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators are pursuing an upfront approval for eltrombopag in combination with immunosuppressive therapy for the treatment of severe aplastic anemia (SAA).

Based on eltrombopag’s single-agent activity in refractory SAA, they hypothesized that its addition to standard immunosuppressive therapy of horse antithymocyte globulin (hATG) and cyclosporine (CsA) in the first-line setting could improve patient outcome.

And, in a phase 2 trial, it did.

“The addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” said Danielle

Townsley, MD, who presented the data at the 2015 ASH Annual Meeting.

Dr Townsley, of the National Heart, Lung, and Blood Institute, National Institutes of Health, in Bethesda, Maryland, presented the findings as abstract LBA-2.*

The US Food and Drug Administration approved eltrombopag to treat refractory SAA in November 2014, and the European Commission approved it in 2015.

Investigators believed eltrombopag in the upfront, treatment-naïve setting could yield higher overall response rates (ORRs) than the 60% to 70% achieved with standard immunosuppressives worldwide.

“[It was] logical to consider treating patients early at the start of their disease,” Dr Townsley said.

So she and her colleagues conducted an investigator-initiated, phase 2, single-center trial of eltrombopag combined with immunosuppressive agents for first-line treatment of SAA.

Study design and patient population

Patients had to have confirmed treatment-naïve SAA, be a minimum of 2 years old, and weigh more than 12 kg. They were excluded if they had prior immunosuppressive therapy with ATG, alemtuzumab, or cyclophosphamide. They were also excluded if they had liver cirrhosis, AST/ALT more than 5 times normal, or Fanconi anemia.

Primary endpoints of the study were complete response (CR) at 6 months and toxicity. Secondary endpoints included ORR and partial response (PR) rate, survival, clonal evolution, and relapse.

Investigators defined CR as having an absolute neutrophil count (ANC) of 1000/μL or higher, a hemoglobin level of 10 g/dL or higher, and a platelet count of 100,000/μL or higher. They defined PR as blood counts no longer meeting criteria for SAA or CR.

All 92 patients received standard hATG (on days 1 to 4) and CsA (for 6 months). Patients in cohort 1 (n=30) also received eltrombopag at 150 mg daily, starting on day 14 for 6 months.

Patients in cohort 2 (n=31) received eltrombopag at 150 mg daily, starting on day 14 for 3 months. And the 31 patients in cohort 3 started 150 mg of daily eltrombopag simultaneously with the immunosuppressants and continued to receive the drug for 6 months.

Investigators assessed response at 3 and 6 months and planned to follow patients for at least 5 years.

Patients in all cohorts were a median of 32 years (range, 3–82), with 21% being younger than 18. About half were male, 66% had less than 1% of a paroxysmal nocturnal hemoglobinuria clone, 37% had a median neutrophil count less than 200/μL, a median reticulocyte count of 20,000/μL (range, 1600–60,400/μL), and a median platelet count of 9000/μL (range, 0–37,000/μL).

Results

At 3 months, the ORR for the entire population was 81%, and the CR rate was 28%. The ORR was 77% in cohorts 1 and 2 and 92% in cohort 3. The CR rate was 17%, 26%, and 44% in cohorts 1, 2, and 3, respectively.

At 6 months, the ORR for the entire population was 86%, and the CR rate was 37%. The ORR was 80%, 87%, and 95% in cohorts 1, 2, and 3, respectively. And the CR rate was 33%, 26%, and 60%, respectively.

Compared to historic rates for patients on hATG and CsA alone, “the addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” Dr Townsley said.

“And for cohort 3, when eltrombopag is given on day 1, the rate of response in evaluable patients to date appears even higher, with 95% overall response rate at 6 months, of which 60% are complete.”

Dr Townsley also noted that, compared to historical experience, neutrophil recovery was more robust in responding patients treated with eltrombopag. Patients on eltrombopag had a mean ANC of 2253/μL, compared with an ANC of 1716/μL for the historic comparator.

“And likewise, more robust platelet recovery was observed with eltrombopag,” Dr Townsley said, with the eltrombopag-treated patients achieving a mean count of 115,262/μL, compared to a mean of 84,303/μL for the historic group.

She added that, among all eltrombopag-treated patients, the median time to neutrophil recovery was 29 days for an ANC greater than 200/μL and 47 days for an ANC greater than 500/μL. In cohort 3—in which eltrombopag was initiated on day 1—those endpoints were achieved in a median of 8 days and 38 days, respectively.

Patients became transfusion-independent for red cells in a median of 42 days and for platelets in a median of 32 days.

Eltrombopag-treated patients had a 99% overall survival at a median follow-up of 18 months (range 1 – 42) when censored for stem cell transplant. When not censored for transplant, their overall survival was 97%.

Adverse events

“The addition of eltrombopag to ATG and cyclosporine was, overall, well tolerated,” Dr Townsley said. “Few grade 3 to 4 events were attributed to eltrombopag.”

Severe cutaneous reactions in 2 patients caused eltrombopag to be stopped, and 10% of patients had grade 2–3 transaminase and bilirubin elevations.

Bone marrow biopsies revealed no increased fibrosis.

One patient with thymoma died while on study due to encephalopathy. And 2 deaths occurred after hematopoietic stem cell transplant, one with relapsed acute myeloid leukemia and the other from relapsed aplastic anemia.

Clonal evolution occurred in 7 patients, 2 who had achieved CR and evolved in 3 and 30 months. Neither patient had bone marrow dysplasia. One patient’s cytogenetics normalized, and the other had stable disease.

“In our protocol, we define any new cytogenetic abnormality as clonal evolution—we have always done this,” Dr Townsley said.

Of the other 5 patients who evolved, 1 achieved a CR and relapsed, 1 achieved a PR and relapsed, 2 achieved a PR, and 1 had no response. Three of these patients had stem cell transplants, 1 had stable disease, and 1 died of acute myeloid leukemia after stem cell transplant.

The investigators concluded that eltrombopag increases complete and overall hematologic response rates in treatment-naïve SAA patients. Immediate introduction of eltrombopag with immunosuppressant therapy may be optimal, and CR does not appear to prevent clonal evolution.

Investigators are currently in the process of conducting a long-term, serial genomic analysis. The study is open for accrual to an extension cohort.

Eltrombopag is marketed as Promacta in the US and Revolade in most countries outside the US.

Dr Townsley disclosed drug and research funding from GlaxoSmithKline and Novartis, developers of eltrombopag.

*Data in the abstract differ from the presentation.

Danielle Townsley, MD

Photo courtesy of ASH

ORLANDO, FL—Investigators are pursuing an upfront approval for eltrombopag in combination with immunosuppressive therapy for the treatment of severe aplastic anemia (SAA).

Based on eltrombopag’s single-agent activity in refractory SAA, they hypothesized that its addition to standard immunosuppressive therapy of horse antithymocyte globulin (hATG) and cyclosporine (CsA) in the first-line setting could improve patient outcome.

And, in a phase 2 trial, it did.

“The addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” said Danielle

Townsley, MD, who presented the data at the 2015 ASH Annual Meeting.

Dr Townsley, of the National Heart, Lung, and Blood Institute, National Institutes of Health, in Bethesda, Maryland, presented the findings as abstract LBA-2.*

The US Food and Drug Administration approved eltrombopag to treat refractory SAA in November 2014, and the European Commission approved it in 2015.

Investigators believed eltrombopag in the upfront, treatment-naïve setting could yield higher overall response rates (ORRs) than the 60% to 70% achieved with standard immunosuppressives worldwide.

“[It was] logical to consider treating patients early at the start of their disease,” Dr Townsley said.

So she and her colleagues conducted an investigator-initiated, phase 2, single-center trial of eltrombopag combined with immunosuppressive agents for first-line treatment of SAA.

Study design and patient population

Patients had to have confirmed treatment-naïve SAA, be a minimum of 2 years old, and weigh more than 12 kg. They were excluded if they had prior immunosuppressive therapy with ATG, alemtuzumab, or cyclophosphamide. They were also excluded if they had liver cirrhosis, AST/ALT more than 5 times normal, or Fanconi anemia.

Primary endpoints of the study were complete response (CR) at 6 months and toxicity. Secondary endpoints included ORR and partial response (PR) rate, survival, clonal evolution, and relapse.

Investigators defined CR as having an absolute neutrophil count (ANC) of 1000/μL or higher, a hemoglobin level of 10 g/dL or higher, and a platelet count of 100,000/μL or higher. They defined PR as blood counts no longer meeting criteria for SAA or CR.

All 92 patients received standard hATG (on days 1 to 4) and CsA (for 6 months). Patients in cohort 1 (n=30) also received eltrombopag at 150 mg daily, starting on day 14 for 6 months.

Patients in cohort 2 (n=31) received eltrombopag at 150 mg daily, starting on day 14 for 3 months. And the 31 patients in cohort 3 started 150 mg of daily eltrombopag simultaneously with the immunosuppressants and continued to receive the drug for 6 months.

Investigators assessed response at 3 and 6 months and planned to follow patients for at least 5 years.

Patients in all cohorts were a median of 32 years (range, 3–82), with 21% being younger than 18. About half were male, 66% had less than 1% of a paroxysmal nocturnal hemoglobinuria clone, 37% had a median neutrophil count less than 200/μL, a median reticulocyte count of 20,000/μL (range, 1600–60,400/μL), and a median platelet count of 9000/μL (range, 0–37,000/μL).

Results

At 3 months, the ORR for the entire population was 81%, and the CR rate was 28%. The ORR was 77% in cohorts 1 and 2 and 92% in cohort 3. The CR rate was 17%, 26%, and 44% in cohorts 1, 2, and 3, respectively.

At 6 months, the ORR for the entire population was 86%, and the CR rate was 37%. The ORR was 80%, 87%, and 95% in cohorts 1, 2, and 3, respectively. And the CR rate was 33%, 26%, and 60%, respectively.

Compared to historic rates for patients on hATG and CsA alone, “the addition of eltrombopag resulted in over 20% higher overall response rates and complete response rates for both 3 and 6 months,” Dr Townsley said.

“And for cohort 3, when eltrombopag is given on day 1, the rate of response in evaluable patients to date appears even higher, with 95% overall response rate at 6 months, of which 60% are complete.”

Dr Townsley also noted that, compared to historical experience, neutrophil recovery was more robust in responding patients treated with eltrombopag. Patients on eltrombopag had a mean ANC of 2253/μL, compared with an ANC of 1716/μL for the historic comparator.

“And likewise, more robust platelet recovery was observed with eltrombopag,” Dr Townsley said, with the eltrombopag-treated patients achieving a mean count of 115,262/μL, compared to a mean of 84,303/μL for the historic group.

She added that, among all eltrombopag-treated patients, the median time to neutrophil recovery was 29 days for an ANC greater than 200/μL and 47 days for an ANC greater than 500/μL. In cohort 3—in which eltrombopag was initiated on day 1—those endpoints were achieved in a median of 8 days and 38 days, respectively.

Patients became transfusion-independent for red cells in a median of 42 days and for platelets in a median of 32 days.

Eltrombopag-treated patients had a 99% overall survival at a median follow-up of 18 months (range 1 – 42) when censored for stem cell transplant. When not censored for transplant, their overall survival was 97%.

Adverse events

“The addition of eltrombopag to ATG and cyclosporine was, overall, well tolerated,” Dr Townsley said. “Few grade 3 to 4 events were attributed to eltrombopag.”

Severe cutaneous reactions in 2 patients caused eltrombopag to be stopped, and 10% of patients had grade 2–3 transaminase and bilirubin elevations.

Bone marrow biopsies revealed no increased fibrosis.

One patient with thymoma died while on study due to encephalopathy. And 2 deaths occurred after hematopoietic stem cell transplant, one with relapsed acute myeloid leukemia and the other from relapsed aplastic anemia.

Clonal evolution occurred in 7 patients, 2 who had achieved CR and evolved in 3 and 30 months. Neither patient had bone marrow dysplasia. One patient’s cytogenetics normalized, and the other had stable disease.

“In our protocol, we define any new cytogenetic abnormality as clonal evolution—we have always done this,” Dr Townsley said.

Of the other 5 patients who evolved, 1 achieved a CR and relapsed, 1 achieved a PR and relapsed, 2 achieved a PR, and 1 had no response. Three of these patients had stem cell transplants, 1 had stable disease, and 1 died of acute myeloid leukemia after stem cell transplant.

The investigators concluded that eltrombopag increases complete and overall hematologic response rates in treatment-naïve SAA patients. Immediate introduction of eltrombopag with immunosuppressant therapy may be optimal, and CR does not appear to prevent clonal evolution.

Investigators are currently in the process of conducting a long-term, serial genomic analysis. The study is open for accrual to an extension cohort.

Eltrombopag is marketed as Promacta in the US and Revolade in most countries outside the US.

Dr Townsley disclosed drug and research funding from GlaxoSmithKline and Novartis, developers of eltrombopag.

*Data in the abstract differ from the presentation.

Russel Ware, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.

The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Because of these findings, the trial was terminated early, in November of last year.

Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.

“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”

Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.

Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.

Study design

For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.

All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.

In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.

In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.

The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.

Results

In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.

“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.

In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.

In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 10⁹/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.

“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.

“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”

Early termination and noninferiority

Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.

At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.

The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10^-16. By post-hoc analysis, the P value for superiority was 0.023.

Secondary endpoints

There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.

There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).

Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).

Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.

The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.

Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.

*Data in the abstract differ from data presented at the meeting.

Russel Ware, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.

The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Because of these findings, the trial was terminated early, in November of last year.

Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.

“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”

Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.

Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.

Study design

For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.

All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.

In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.

In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.

The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.

Results

In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.

“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.

In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.

In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 10⁹/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.

“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.

“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”

Early termination and noninferiority

Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.

At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.

The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10^-16. By post-hoc analysis, the P value for superiority was 0.023.

Secondary endpoints

There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.

There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).

Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).

Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.

The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.

Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.

*Data in the abstract differ from data presented at the meeting.

Russel Ware, MD, PhD

Photo courtesy of ASH

ORLANDO, FL—Hydroxyurea (HU) is noninferior to chronic blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), results of the TWiTCH trial suggest.

The trial showed that daily doses of HU lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Because of these findings, the trial was terminated early, in November of last year.

Last week, results from TWiTCH were presented at the 2015 ASH Annual Meeting (abstract 3*) and published in The Lancet. The study was funded by the National Heart Lung and Blood Institute.

“Stroke . . . is one of the most severe and catastrophic clinical events that occurs in children with sickle cell, with serious motor and cognitive sequelae,” said study investigator and ASH presenter Russell E. Ware, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“With the advent of TCD, we now have the ability to identify high-risk children and use chronic transfusion therapy to prevent primary stroke.”

Dr Ware noted that results of the STOP trial showed that chronic transfusion reduced the risk of stroke in high-risk children with SCD, but the transfusions could not be stopped. The STOP 2 trial confirmed this, showing that stopping transfusions led to an increase in TCD blood velocity and stroke risk.

Because transfusions must be continued indefinitely and are associated with morbidity, an alternative stroke prevention strategy is needed, Dr Ware said. He and his colleagues conducted the TWiTCH trial to determine if HU would fit the bill.

Study design

For this phase 3 study, the researchers compared 24 months of transfusions to HU in children with SCD and abnormal TCD velocities. Study enrollment began in September 2011 and ended in April 2013.

All eligible children had received at least 12 months of transfusions prior to enrollment. They were randomized 1:1 to continue receiving transfusions or to receive the maximum-tolerated dose (MTD) of HU.

In the transfusion arm, the goal was to keep hemoglobin S levels below 30%, and iron overload was managed with daily oral chelation.

In the HU arm, the drug was escalated to the MTD, and children continued receiving transfusions until the MTD was achieved. Iron overload was managed with monthly phlebotomy.

The study had a noninferiority design, and the primary endpoint was the 24-month TCD velocity (with a noninferiority margin of 15 cm/sec). TCD velocities were obtained every 12 weeks and reviewed centrally. Local researchers were masked to the results.

Results

In all, 121 children were randomized—61 to transfusions and 60 to HU. Patient characteristics—baseline TCD velocities, age, duration of transfusion, etc.—were well balanced between the treatment arms.

“The average age of the patients was 9 or 10 years old, with about 3 or 4 years of transfusions coming in to the study,” Dr Ware noted.

In the transfusion arm, the children maintained a hemoglobin level of about 9 g/dL and hemoglobin S levels of less than 30%. Most patients received chelation with deferasirox at 26 ±6 mg/kg/day.

In the HU arm, 57 of 60 patients reached the MTD, which was 27 ± 4 mg/kg/day, on average. The median transfusion overlap was 6 months, the average absolute neutrophil count was 3.5 ± 1.6 x 10⁹/L, the average hemoglobin was about 9 g/dL, and fetal hemoglobin rose to about 25%. There were 756 phlebotomy procedures performed in 54 children.

“[In the HU arm,] very quickly after enrollment, the sickle hemoglobin rises, as the transfusions are weaned,” Dr Ware noted.

“Commensurately, the hemoglobin F rises as a protection. The neutrophil count and reticulocyte count drops, and those curves [counts in the HU and transfusion arms] diverge fairly quickly. The serum ferritin [curves] diverged as well.”

Early termination and noninferiority

Interim data analyses were scheduled to take place after one-third of the patients had exited the study and after two-thirds had exited. The first interim analysis demonstrated noninferiority, and the trial was closed early. An analysis was repeated after half of the patients had exited the study, and the trial was terminated.

At that point, 42 children had completed 24 months of treatment in the transfusion arm, 11 patients had truncated treatment, and 8 had early exits. Forty-one patients had completed 24 months of therapy in the HU arm, 13 had truncated treatment, and 6 had early exits.

The final TCD velocity (mean ± standard error) was 143 ± 1.6 cm/sec in the transfusion arm and 138 ± 1.6 cm/sec in the HU arm. The P value for noninferiority (in the intent-to-treat population) was 8.82 x 10^-16. By post-hoc analysis, the P value for superiority was 0.023.

Secondary endpoints

There were 29 new neurological events during the trial—12 in the transfusion arm and 17 in the HU arm. There were no new strokes, but there were 6 new transient ischemic attacks—3 in each arm.

There were no new cerebral infarcts in either arm. But there was 1 new progressive vasculopathy in the transfusion arm. And 1 child in the transfusion arm was withdrawn from the study for increasing TCD (>240 cm/sec).

Iron overload improved more in the HU arm than the transfusion arm, with a greater average change in both serum ferritin (P<0.001) and liver iron concentration (P=0.001).

Serious adverse events were more common in the HU arm than the transfusion arm—23 events in 9 patients and 10 events in 6 patients, respectively. But none of these events were thought to be related to study treatment or procedures.

The most common serious adverse event in both groups was vaso-occlusive pain—11 events in 5 HU-treated patients and 3 events in 1 transfusion-treated patient.

Dr Ware noted that there were no secondary leukemias associated with HU in this trial, and there is “a cumulative body of evidence” spanning 20 years that suggests the drug is not carcinogenic in this patient population.

*Data in the abstract differ from data presented at the meeting.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.

Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.

Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.

“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”

“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”

“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”

In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.

The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.

Patients and treatment

In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Response and survival

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.

Characteristics of response

For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.

Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.

Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m². At the end of treatment, the median dose was 4.0 mg/m² (P=0.023).

“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”

Adverse events and death

No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.

There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Infections

“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”

“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”

There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.

Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).

Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.

The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.

“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”

“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”

*Data in the abstract differ from data presented at the meeting.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.

Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.

Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.

“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”

“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”

“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”

In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.

The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.

Patients and treatment

In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Response and survival

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.

Characteristics of response

For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.

Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.

Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m². At the end of treatment, the median dose was 4.0 mg/m² (P=0.023).

“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”

Adverse events and death

No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.

There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Infections

“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”

“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”

There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.

Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).

Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.

The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.

“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”

“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”

*Data in the abstract differ from data presented at the meeting.

Attendees at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.

Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.

Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.

Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.

“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”

“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”

“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”

In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.

The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.

Patients and treatment

In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Response and survival

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT are still alive.

Characteristics of response

For some patients, response to NI-0501 included a significant improvement in neutrophil count (8/10, P<0.001), platelet count (7/12, P<0.001), and ferritin level (P=0.0025). The median serum ferritin level was 4142 ng/mL at baseline and 1648 ng/mL at the end of treatment.

Both patients who were febrile at the start of treatment experienced rapid normalization of fever. Six of 7 patients with palpable spleen or liver at the start of treatment had an improvement in organomegaly. And 3 of 4 patients had resolution or improvement of CNS involvement.

Overall, there was a significant decrease in glucocorticoid dose. The median dose at baseline was 10.0 mg/m². At the end of treatment, the median dose was 4.0 mg/m² (P=0.023).

“One pharmacodynamic readout that’s useful for understanding IFNγ biology in vivo is CXCL9,” Dr Jordan noted. “This is secreted by mononuclear phagocytes in response to IFNγ. And most patients had a very clear fall in CXCL9 while receiving NI-0501.”

Adverse events and death

No off-target effects of NI-0501 have been observed, and none of the patients have withdrawn from the study for safety reasons.

There have been 14 serious adverse events in 8 patients, but only 1 of these events was considered treatment-related. The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

In all, 3 patients have died, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Infections

“[NI-0501 provides] a targeted form of immune suppression, so we can expect that most concerns will be related to infection,” Dr Jordan said. “The effects of IFNγ on immune defense are actually predictable, and they’re predictable because of 2 patient populations.”

“First are the rare patients who are born with IFNγ-receptor deficiency, and second are individuals that develop neutralizing autoantibodies against IFNγ. Both patient populations experience infections with atypical mycobacteria, tuberculosis, Salmonella, and so forth.”

There were 10 infections already present at the start of the study—St epidermidis (n=1), C difficile (n=1), E coli (n=1, gram-positive), cytomegalovirus (n=1), Epstein-Barr virus (n=4), and parvovirus (n=1). All of these infections resolved with treatment.

Fourteen infections arose during the study course—St epidermidis (n=1), C difficile (n=1), P aeruginosa (n=1), K pneumoniae (n=1), E coli (1 gram-positive, 1 gram-negative), adenovirus (n=1), cytomegalovirus (n=2), Epstein-Barr virus (1 reactivation), parvovirus (1 reactivation), parainfluenza T3 (n=1), influenza A (n=1), and Candida (n=1).

Most of these infections resolved. The exceptions were the case of adenovirus, 1 case of cytomegalovirus (although there was improvement), the Epstein-Barr virus reactivation, the parvovirus reactivation (though improved), and the case of influenza A.

The researchers did not know if the parainfluenza T3 infection resolved. The patient’s viral status was not reassessed prior to death.

“So, in conclusion, NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Dr Jordan said. “The response to this agent appears to be independent of the underlying causative mutation. It’s also independent of the presence and type of infectious trigger.”

“NI-0501 was very well-tolerated. No safety concerns have emerged to date, and no infections known to be caused by deficiency of IFNγ have been observed. The neutralization of IFNγ by NI-0501 can offer an innovative and targeted approach to the management of HLH.”

*Data in the abstract differ from data presented at the meeting.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

Treatment with the antiplatelet agent prasugrel does not significantly reduce the rate of pain crises or severe lung complications in children with sickle cell disease (SCD), according to one of the largest and most geographically diverse international trials on SCD to date.

The DOVE trial was a double blind, randomized, placebo-controlled phase 3 study conducted at 51 sites across 13 nations in the Americas, Europe, the Middle East, Asia, and Africa.

“Although we were disappointed that prasugrel does not appear to ease the suffering of children with sickle cell disease, the fact that this study incorporated patients in the wide range of countries where the disease occurs is hugely significant,” said Carolyn Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California.

“The logistical challenges that we addressed in designing and implementing the study can serve as a model for future research.”

The results of the study were published in NEJM. The research was sponsored by Daiichi Sankyo Company, Ltd. and Eli Lilly and Company.

The goal of the DOVE trial was to determine whether prasugrel could significantly reduce the rate of vaso-occlusive crises (VOCs)—defined as pain crises or acute chest syndrome—in children with SCD.

The trial enrolled 341 patients. About half of them (n=170) received daily oral prasugrel for between 9 and 24 months at individualized, blinded doses intended to maintain a selected target range of platelet activity. The remaining patients received a placebo.

All patients were monitored for VOCs prompting medical visits and for any increased risk of bleeding due to reduced platelet activity. In addition, patients 4 years old and older kept a daily electronic pain diary to aid in the reporting of painful events between visits.

At the end of the study period, there was no significant difference between the treatment arms in the overall rate of VOCs. The rate was 2.3 episodes per person-year in the prasugrel arm and 2.8 episodes per person-year in the placebo arm (P=0.12).

Similarly, prasugrel did not have a significant effect on the trial’s secondary outcome measures—VOC-related hospitalization rate, duration of hospitalization, time between VOCs, incidence of ischemic attack or ischemic stroke, transfusion rate, rate of pain, intensity of pain, use of analgesics, or missed school due to SCD-related pain.

The data did reveal a trend toward reduced VOC rates among patients ages 12 to 18 (P=0.06) and among patients who were not taking hydroxyurea (P=0.06). However, these trends were not statistically significant and require further research to determine their validity.

The investigators noted no adverse events related to prasugrel.

“Even though prasugrel did not achieve significant results, the findings should not detract from the fact that this team successfully completed a rigorous, sophisticated trial in a disease where the barriers to conducting large-scale international, patient-focused research are quite high,” said Matthew M. Heeney, MD, of the Dana–Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.

To conduct the study successfully on such a broad geographical scale, the investigators had to address several obstacles, such as varying standards of care, local technological resources, and infrastructure challenges, such as a lack of reliable electrical power.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

Treatment with the antiplatelet agent prasugrel does not significantly reduce the rate of pain crises or severe lung complications in children with sickle cell disease (SCD), according to one of the largest and most geographically diverse international trials on SCD to date.

The DOVE trial was a double blind, randomized, placebo-controlled phase 3 study conducted at 51 sites across 13 nations in the Americas, Europe, the Middle East, Asia, and Africa.

“Although we were disappointed that prasugrel does not appear to ease the suffering of children with sickle cell disease, the fact that this study incorporated patients in the wide range of countries where the disease occurs is hugely significant,” said Carolyn Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California.

“The logistical challenges that we addressed in designing and implementing the study can serve as a model for future research.”

The results of the study were published in NEJM. The research was sponsored by Daiichi Sankyo Company, Ltd. and Eli Lilly and Company.

The goal of the DOVE trial was to determine whether prasugrel could significantly reduce the rate of vaso-occlusive crises (VOCs)—defined as pain crises or acute chest syndrome—in children with SCD.

The trial enrolled 341 patients. About half of them (n=170) received daily oral prasugrel for between 9 and 24 months at individualized, blinded doses intended to maintain a selected target range of platelet activity. The remaining patients received a placebo.

All patients were monitored for VOCs prompting medical visits and for any increased risk of bleeding due to reduced platelet activity. In addition, patients 4 years old and older kept a daily electronic pain diary to aid in the reporting of painful events between visits.

At the end of the study period, there was no significant difference between the treatment arms in the overall rate of VOCs. The rate was 2.3 episodes per person-year in the prasugrel arm and 2.8 episodes per person-year in the placebo arm (P=0.12).

Similarly, prasugrel did not have a significant effect on the trial’s secondary outcome measures—VOC-related hospitalization rate, duration of hospitalization, time between VOCs, incidence of ischemic attack or ischemic stroke, transfusion rate, rate of pain, intensity of pain, use of analgesics, or missed school due to SCD-related pain.

The data did reveal a trend toward reduced VOC rates among patients ages 12 to 18 (P=0.06) and among patients who were not taking hydroxyurea (P=0.06). However, these trends were not statistically significant and require further research to determine their validity.

The investigators noted no adverse events related to prasugrel.

“Even though prasugrel did not achieve significant results, the findings should not detract from the fact that this team successfully completed a rigorous, sophisticated trial in a disease where the barriers to conducting large-scale international, patient-focused research are quite high,” said Matthew M. Heeney, MD, of the Dana–Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.

To conduct the study successfully on such a broad geographical scale, the investigators had to address several obstacles, such as varying standards of care, local technological resources, and infrastructure challenges, such as a lack of reliable electrical power.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

Treatment with the antiplatelet agent prasugrel does not significantly reduce the rate of pain crises or severe lung complications in children with sickle cell disease (SCD), according to one of the largest and most geographically diverse international trials on SCD to date.

The DOVE trial was a double blind, randomized, placebo-controlled phase 3 study conducted at 51 sites across 13 nations in the Americas, Europe, the Middle East, Asia, and Africa.

“Although we were disappointed that prasugrel does not appear to ease the suffering of children with sickle cell disease, the fact that this study incorporated patients in the wide range of countries where the disease occurs is hugely significant,” said Carolyn Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California.

“The logistical challenges that we addressed in designing and implementing the study can serve as a model for future research.”

The results of the study were published in NEJM. The research was sponsored by Daiichi Sankyo Company, Ltd. and Eli Lilly and Company.

The goal of the DOVE trial was to determine whether prasugrel could significantly reduce the rate of vaso-occlusive crises (VOCs)—defined as pain crises or acute chest syndrome—in children with SCD.

The trial enrolled 341 patients. About half of them (n=170) received daily oral prasugrel for between 9 and 24 months at individualized, blinded doses intended to maintain a selected target range of platelet activity. The remaining patients received a placebo.

All patients were monitored for VOCs prompting medical visits and for any increased risk of bleeding due to reduced platelet activity. In addition, patients 4 years old and older kept a daily electronic pain diary to aid in the reporting of painful events between visits.

At the end of the study period, there was no significant difference between the treatment arms in the overall rate of VOCs. The rate was 2.3 episodes per person-year in the prasugrel arm and 2.8 episodes per person-year in the placebo arm (P=0.12).

Similarly, prasugrel did not have a significant effect on the trial’s secondary outcome measures—VOC-related hospitalization rate, duration of hospitalization, time between VOCs, incidence of ischemic attack or ischemic stroke, transfusion rate, rate of pain, intensity of pain, use of analgesics, or missed school due to SCD-related pain.

The data did reveal a trend toward reduced VOC rates among patients ages 12 to 18 (P=0.06) and among patients who were not taking hydroxyurea (P=0.06). However, these trends were not statistically significant and require further research to determine their validity.

The investigators noted no adverse events related to prasugrel.

“Even though prasugrel did not achieve significant results, the findings should not detract from the fact that this team successfully completed a rigorous, sophisticated trial in a disease where the barriers to conducting large-scale international, patient-focused research are quite high,” said Matthew M. Heeney, MD, of the Dana–Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.

To conduct the study successfully on such a broad geographical scale, the investigators had to address several obstacles, such as varying standards of care, local technological resources, and infrastructure challenges, such as a lack of reliable electrical power.

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

[email protected]

On Twitter @maryjodales

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

[email protected]

On Twitter @maryjodales

ORLANDO – Adding eltrombopag to standard immunosuppressive treatment for newly-diagnosed severe aplastic anemia boosted overall response rates from around 65% to over 90%, based on a late-breaker study presented by Dr. Danielle M. Townsley at the annual meeting of the American Society of Hematology.

Dr. Townsley said that starting the combination treatment immediately at diagnosis, rather than waiting to introduce eltrombopag at either 2 weeks or 3 months after initiating standard immunosuppressive therapy, was associated with better outcomes. As a result of the findings, a cohort extension of the trial will continue and is enrolling patients.

In our video interview, Dr. Townsley discusses the top-level results and says that it’s too early to introduce the protocol into practice outside a clinical trial. She urges hematologists to enroll their patients in the ongoing cohort study.

[email protected]

On Twitter @maryjodales

Platelet inhibitor prasugrel has failed to show a significant reduction in the rate of vaso-occlusive crises events in children and adolescents with sickle cell anemia, according to data presented Dec. 8 at the annual meeting of the American Society of Hematology.

The phase III randomized placebo-controlled trial of 341 children and adolescents (aged 2-17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultaneously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduction among the older patients aged 12-17 years.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospitalizations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group (N Engl J Med. 2015, Dec 8. doi: 10.1056/NEJMoa1512021).

“Sickle cell anemia is a heterogeneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr. Matthew M. Heeney of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and his coauthors.

“However, the nonsignificant effect of prasugrel in the oldest age group may suggest that platelet activation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.”

Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceutical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

Platelet inhibitor prasugrel has failed to show a significant reduction in the rate of vaso-occlusive crises events in children and adolescents with sickle cell anemia, according to data presented Dec. 8 at the annual meeting of the American Society of Hematology.

The phase III randomized placebo-controlled trial of 341 children and adolescents (aged 2-17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultaneously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduction among the older patients aged 12-17 years.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospitalizations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group (N Engl J Med. 2015, Dec 8. doi: 10.1056/NEJMoa1512021).

“Sickle cell anemia is a heterogeneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr. Matthew M. Heeney of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and his coauthors.

“However, the nonsignificant effect of prasugrel in the oldest age group may suggest that platelet activation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.”

Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceutical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

Platelet inhibitor prasugrel has failed to show a significant reduction in the rate of vaso-occlusive crises events in children and adolescents with sickle cell anemia, according to data presented Dec. 8 at the annual meeting of the American Society of Hematology.

The phase III randomized placebo-controlled trial of 341 children and adolescents (aged 2-17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultaneously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduction among the older patients aged 12-17 years.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospitalizations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group (N Engl J Med. 2015, Dec 8. doi: 10.1056/NEJMoa1512021).

“Sickle cell anemia is a heterogeneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr. Matthew M. Heeney of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and his coauthors.

“However, the nonsignificant effect of prasugrel in the oldest age group may suggest that platelet activation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.”

Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceutical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

Blood for transfusion

Photo by Elise Amendola

ORLANDO, FL—The storage duration of red blood cells (RBCs) doesn’t affect transfusion outcomes in children with lactic acidosis due to severe anemia, according to a new study.

Investigators found no significant differences in lactate levels, 30-day recovery, survival, or adverse events between children who received RBCs stored for 25 to 35 days and children who received RBCs stored for 1 to 10 days.

These results were published in JAMA and presented at the 2015 ASH Annual Meeting as abstract 769.

Christine Cserti-Gazdewich, MD, of University Health Network in Toronto, Canada, provided insights on the data during a press conference at ASH.

A concern of the investigators, according to Dr Cserti-Gazdewich, was that previous studies on blood storage were conducted in “high-income countries in high-technology care settings with blood inventory wealth, and findings may not be generalizable to the other half of the world.”

She pointed out that, in less developed countries, the shortfall in blood availability compared to the need is up to 3-fold.

So the investigators examined whether longer-stored red blood cells actually deliver oxygen in a manner not worse than shorter-stored or fresh blood and examined it at the extremes of storage duration in the context of a very high-dose need.

The team evaluated 290 children (aged 6 months to 60 months) with elevated blood lactate levels due to severe anemia who presented at a university-affiliated national referral hospital in Kampala, Uganda.

The children were randomized to receive RBC units stored for 25 to 35 days (longer-storage group, n=145) or RBCs stored for 1 to 10 days (shorter-storage group, n=145).

All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.

In the entire population, the mean presenting hemoglobin level was 3.7 g/dL, and the mean lactate level was 9.3 mmol/L. The median RBC unit storage duration was 8 days (range, 7-9) for the shorter-storage group and 32 days (range, 30-34) for the longer-storage group.

Results

The investigators found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days.

The study’s primary endpoint was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours, using a margin of noninferiority equal to an absolute difference of 25%.

The proportion of patients meeting this endpoint was 0.61 in the longer-storage group and 0.58 in the shorter-storage group (P<0.001 for noninferiority).

Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. And there was no statistical difference in the median time to achieve a blood lactate of 3 mmol/L or lower at 4 hours (hazard ratio=0.99, P=0.92).

Cerebral tissue oxygen saturation rose significantly during transfusion, but there was no significant difference between the 2 storage groups. The median area under the curve of cerebral tissue oxygen saturation during transfusion was 679 (range, 334-1156) for the longer-storage group and 521 (range, 303-835) for the shorter-storage group (P=0.25).

There was no significant difference between the longer-storage group and the shorter-storage group in the persistence of stupor or coma 8 hours after transfusion (12.6% and 19.6%, respectively, P=0.11) or the persistence of respiratory distress at 8 hours (28.7% and 30%, respectively, P=0.79).

The median length of hospital stay was 4 days (range, 2-6) in the longer-storage group and 4 days (range, 3-7) in the shorter-storage group.

There were 8 deaths, 3 in the longer-storage group and 5 in the shorter-storage group, during the 24 hours from the start of transfusion. Four additional patients, 2 in each group, died in the hospital after the initial 24-hour observation period.

The proportion of patients who had returned to good health by 30 days was 86% of the longer-storage group and 93% of the shorter-storage group (P=0.13).

“By every single measure we explored, and we explored many, we found that long-stored blood was not inferior . . . ,” Dr Csert-Gazdewich said. “We truly found no justification to shorten the current storage duration of red cells as judged by the fundamental role to deliver oxygen.”

Blood for transfusion

Photo by Elise Amendola

ORLANDO, FL—The storage duration of red blood cells (RBCs) doesn’t affect transfusion outcomes in children with lactic acidosis due to severe anemia, according to a new study.

Investigators found no significant differences in lactate levels, 30-day recovery, survival, or adverse events between children who received RBCs stored for 25 to 35 days and children who received RBCs stored for 1 to 10 days.

These results were published in JAMA and presented at the 2015 ASH Annual Meeting as abstract 769.

Christine Cserti-Gazdewich, MD, of University Health Network in Toronto, Canada, provided insights on the data during a press conference at ASH.

A concern of the investigators, according to Dr Cserti-Gazdewich, was that previous studies on blood storage were conducted in “high-income countries in high-technology care settings with blood inventory wealth, and findings may not be generalizable to the other half of the world.”

She pointed out that, in less developed countries, the shortfall in blood availability compared to the need is up to 3-fold.

So the investigators examined whether longer-stored red blood cells actually deliver oxygen in a manner not worse than shorter-stored or fresh blood and examined it at the extremes of storage duration in the context of a very high-dose need.

The team evaluated 290 children (aged 6 months to 60 months) with elevated blood lactate levels due to severe anemia who presented at a university-affiliated national referral hospital in Kampala, Uganda.

The children were randomized to receive RBC units stored for 25 to 35 days (longer-storage group, n=145) or RBCs stored for 1 to 10 days (shorter-storage group, n=145).

All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.

In the entire population, the mean presenting hemoglobin level was 3.7 g/dL, and the mean lactate level was 9.3 mmol/L. The median RBC unit storage duration was 8 days (range, 7-9) for the shorter-storage group and 32 days (range, 30-34) for the longer-storage group.

Results

The investigators found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days.

The study’s primary endpoint was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours, using a margin of noninferiority equal to an absolute difference of 25%.

The proportion of patients meeting this endpoint was 0.61 in the longer-storage group and 0.58 in the shorter-storage group (P<0.001 for noninferiority).

Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. And there was no statistical difference in the median time to achieve a blood lactate of 3 mmol/L or lower at 4 hours (hazard ratio=0.99, P=0.92).

Cerebral tissue oxygen saturation rose significantly during transfusion, but there was no significant difference between the 2 storage groups. The median area under the curve of cerebral tissue oxygen saturation during transfusion was 679 (range, 334-1156) for the longer-storage group and 521 (range, 303-835) for the shorter-storage group (P=0.25).

There was no significant difference between the longer-storage group and the shorter-storage group in the persistence of stupor or coma 8 hours after transfusion (12.6% and 19.6%, respectively, P=0.11) or the persistence of respiratory distress at 8 hours (28.7% and 30%, respectively, P=0.79).

The median length of hospital stay was 4 days (range, 2-6) in the longer-storage group and 4 days (range, 3-7) in the shorter-storage group.

There were 8 deaths, 3 in the longer-storage group and 5 in the shorter-storage group, during the 24 hours from the start of transfusion. Four additional patients, 2 in each group, died in the hospital after the initial 24-hour observation period.

The proportion of patients who had returned to good health by 30 days was 86% of the longer-storage group and 93% of the shorter-storage group (P=0.13).

“By every single measure we explored, and we explored many, we found that long-stored blood was not inferior . . . ,” Dr Csert-Gazdewich said. “We truly found no justification to shorten the current storage duration of red cells as judged by the fundamental role to deliver oxygen.”

Blood for transfusion

Photo by Elise Amendola

ORLANDO, FL—The storage duration of red blood cells (RBCs) doesn’t affect transfusion outcomes in children with lactic acidosis due to severe anemia, according to a new study.

Investigators found no significant differences in lactate levels, 30-day recovery, survival, or adverse events between children who received RBCs stored for 25 to 35 days and children who received RBCs stored for 1 to 10 days.

These results were published in JAMA and presented at the 2015 ASH Annual Meeting as abstract 769.

Christine Cserti-Gazdewich, MD, of University Health Network in Toronto, Canada, provided insights on the data during a press conference at ASH.

A concern of the investigators, according to Dr Cserti-Gazdewich, was that previous studies on blood storage were conducted in “high-income countries in high-technology care settings with blood inventory wealth, and findings may not be generalizable to the other half of the world.”

She pointed out that, in less developed countries, the shortfall in blood availability compared to the need is up to 3-fold.

So the investigators examined whether longer-stored red blood cells actually deliver oxygen in a manner not worse than shorter-stored or fresh blood and examined it at the extremes of storage duration in the context of a very high-dose need.

The team evaluated 290 children (aged 6 months to 60 months) with elevated blood lactate levels due to severe anemia who presented at a university-affiliated national referral hospital in Kampala, Uganda.

The children were randomized to receive RBC units stored for 25 to 35 days (longer-storage group, n=145) or RBCs stored for 1 to 10 days (shorter-storage group, n=145).

All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.

In the entire population, the mean presenting hemoglobin level was 3.7 g/dL, and the mean lactate level was 9.3 mmol/L. The median RBC unit storage duration was 8 days (range, 7-9) for the shorter-storage group and 32 days (range, 30-34) for the longer-storage group.

Results

The investigators found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days.

The study’s primary endpoint was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours, using a margin of noninferiority equal to an absolute difference of 25%.

The proportion of patients meeting this endpoint was 0.61 in the longer-storage group and 0.58 in the shorter-storage group (P<0.001 for noninferiority).

Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. And there was no statistical difference in the median time to achieve a blood lactate of 3 mmol/L or lower at 4 hours (hazard ratio=0.99, P=0.92).

Cerebral tissue oxygen saturation rose significantly during transfusion, but there was no significant difference between the 2 storage groups. The median area under the curve of cerebral tissue oxygen saturation during transfusion was 679 (range, 334-1156) for the longer-storage group and 521 (range, 303-835) for the shorter-storage group (P=0.25).

There was no significant difference between the longer-storage group and the shorter-storage group in the persistence of stupor or coma 8 hours after transfusion (12.6% and 19.6%, respectively, P=0.11) or the persistence of respiratory distress at 8 hours (28.7% and 30%, respectively, P=0.79).

The median length of hospital stay was 4 days (range, 2-6) in the longer-storage group and 4 days (range, 3-7) in the shorter-storage group.

There were 8 deaths, 3 in the longer-storage group and 5 in the shorter-storage group, during the 24 hours from the start of transfusion. Four additional patients, 2 in each group, died in the hospital after the initial 24-hour observation period.

The proportion of patients who had returned to good health by 30 days was 86% of the longer-storage group and 93% of the shorter-storage group (P=0.13).

“By every single measure we explored, and we explored many, we found that long-stored blood was not inferior . . . ,” Dr Csert-Gazdewich said. “We truly found no justification to shorten the current storage duration of red cells as judged by the fundamental role to deliver oxygen.”

ORLANDO – A novel small molecule agent improved hematologic parameters and was associated with significant reduction in sickling of red blood cells in patients with sickle cell disease.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation.

In an interview, Dr. Claire Hemmaway of Queens Hospital in Romford, England, discusses early results from a phase I/II randomized, double-blind, placebo-controlled, parallel-group trial.

ORLANDO – A novel small molecule agent improved hematologic parameters and was associated with significant reduction in sickling of red blood cells in patients with sickle cell disease.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation.

In an interview, Dr. Claire Hemmaway of Queens Hospital in Romford, England, discusses early results from a phase I/II randomized, double-blind, placebo-controlled, parallel-group trial.

ORLANDO – A novel small molecule agent improved hematologic parameters and was associated with significant reduction in sickling of red blood cells in patients with sickle cell disease.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation.

In an interview, Dr. Claire Hemmaway of Queens Hospital in Romford, England, discusses early results from a phase I/II randomized, double-blind, placebo-controlled, parallel-group trial.

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.