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American Society of Hematology (ASH): ASH 2016
VIDEO: Hemophilia B gene therapy maintains factor IX levels averaging 28%
SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.
Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.
Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.
Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
ASH: Novel microcapsules show promise in hemophilia A with inhibitory antibodies
SAN DIEGO – Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in a model of hemophilia A with inhibitory antibodies, Caroline E. Hansen reported at the annual meeting of the American Society of Hematology.
“This is a completely new paradigm that uses platelet biomechanics to target and deliver a drug,” Ms. Hansen said at a press briefing.
To create the microcapsules, the investigators deposited alternatingly charged layers of polyelectrolytes, poly-L-lysine, and poly-L-glutamic acid onto a calcium carbonate core covered with factor VIII and dextran. They added fibrinogen to the final polyelectrolyte layer and then chelated out the innermost core, leaving the dextran layer as a shield between factor VIII and the outside of the microcapsule. Initial in vitro experiments showed that the microcapsules adhered to platelets and were incorporated into fibrin networks when platelets were activated, Ms. Hansen reported. Because the microcapsules only ruptured upon platelet contraction, factor VIII was only delivered to actively forming clots as intended, she added.
As a next step, the researchers perfused recalcified whole blood and platelet-poor plasma into a collagen and tissue factor patch designed to mimic vascular injury, and then measured fibrin fluorescence on the patch. Microcapsules lacking dextran, fibrinogen, or loaded factor VIII did not work – a treated sample and a phosphate-buffered saline (PBS) control yielded statistically similar fibrin production. However, complete microcapsules loaded with 0.01 U/mL factor VIII produced four times more fibrin than systemic infusion of 0.05 U/mL factor VIII.
“These were really promising results but we want to take a step back and see if a clot would form in the presence of inhibitory antibodies,” Ms. Hansen said. Accordingly, they added factor VIII inhibitory antibody 2-76 into blood samples from healthy donors. The microcapsules triggered 2.7 times more fibrin production in this setting than systemic treatment did (P less than .05). “This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies,” Ms. Hansen and her associates concluded in their abstract.
The investigators are now studying the extent to which the microcapsules induce thrombin production, and how agents such as blebbistatin, ROCK, and myosin affect platelet contraction force and the efficiency of the microcapsule.
Ms. Hansen had no disclosures.
SAN DIEGO – Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in a model of hemophilia A with inhibitory antibodies, Caroline E. Hansen reported at the annual meeting of the American Society of Hematology.
“This is a completely new paradigm that uses platelet biomechanics to target and deliver a drug,” Ms. Hansen said at a press briefing.
To create the microcapsules, the investigators deposited alternatingly charged layers of polyelectrolytes, poly-L-lysine, and poly-L-glutamic acid onto a calcium carbonate core covered with factor VIII and dextran. They added fibrinogen to the final polyelectrolyte layer and then chelated out the innermost core, leaving the dextran layer as a shield between factor VIII and the outside of the microcapsule. Initial in vitro experiments showed that the microcapsules adhered to platelets and were incorporated into fibrin networks when platelets were activated, Ms. Hansen reported. Because the microcapsules only ruptured upon platelet contraction, factor VIII was only delivered to actively forming clots as intended, she added.
As a next step, the researchers perfused recalcified whole blood and platelet-poor plasma into a collagen and tissue factor patch designed to mimic vascular injury, and then measured fibrin fluorescence on the patch. Microcapsules lacking dextran, fibrinogen, or loaded factor VIII did not work – a treated sample and a phosphate-buffered saline (PBS) control yielded statistically similar fibrin production. However, complete microcapsules loaded with 0.01 U/mL factor VIII produced four times more fibrin than systemic infusion of 0.05 U/mL factor VIII.
“These were really promising results but we want to take a step back and see if a clot would form in the presence of inhibitory antibodies,” Ms. Hansen said. Accordingly, they added factor VIII inhibitory antibody 2-76 into blood samples from healthy donors. The microcapsules triggered 2.7 times more fibrin production in this setting than systemic treatment did (P less than .05). “This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies,” Ms. Hansen and her associates concluded in their abstract.
The investigators are now studying the extent to which the microcapsules induce thrombin production, and how agents such as blebbistatin, ROCK, and myosin affect platelet contraction force and the efficiency of the microcapsule.
Ms. Hansen had no disclosures.
SAN DIEGO – Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in a model of hemophilia A with inhibitory antibodies, Caroline E. Hansen reported at the annual meeting of the American Society of Hematology.
“This is a completely new paradigm that uses platelet biomechanics to target and deliver a drug,” Ms. Hansen said at a press briefing.
To create the microcapsules, the investigators deposited alternatingly charged layers of polyelectrolytes, poly-L-lysine, and poly-L-glutamic acid onto a calcium carbonate core covered with factor VIII and dextran. They added fibrinogen to the final polyelectrolyte layer and then chelated out the innermost core, leaving the dextran layer as a shield between factor VIII and the outside of the microcapsule. Initial in vitro experiments showed that the microcapsules adhered to platelets and were incorporated into fibrin networks when platelets were activated, Ms. Hansen reported. Because the microcapsules only ruptured upon platelet contraction, factor VIII was only delivered to actively forming clots as intended, she added.
As a next step, the researchers perfused recalcified whole blood and platelet-poor plasma into a collagen and tissue factor patch designed to mimic vascular injury, and then measured fibrin fluorescence on the patch. Microcapsules lacking dextran, fibrinogen, or loaded factor VIII did not work – a treated sample and a phosphate-buffered saline (PBS) control yielded statistically similar fibrin production. However, complete microcapsules loaded with 0.01 U/mL factor VIII produced four times more fibrin than systemic infusion of 0.05 U/mL factor VIII.
“These were really promising results but we want to take a step back and see if a clot would form in the presence of inhibitory antibodies,” Ms. Hansen said. Accordingly, they added factor VIII inhibitory antibody 2-76 into blood samples from healthy donors. The microcapsules triggered 2.7 times more fibrin production in this setting than systemic treatment did (P less than .05). “This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies,” Ms. Hansen and her associates concluded in their abstract.
The investigators are now studying the extent to which the microcapsules induce thrombin production, and how agents such as blebbistatin, ROCK, and myosin affect platelet contraction force and the efficiency of the microcapsule.
Ms. Hansen had no disclosures.
AT ASH 2016
Key clinical point: Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in an in vitro model of hemophilia A with inhibitory antibodies.
Major finding: In an in vitro model of this disease state, the microcapsules triggered 2.7 times more fibrin production than systemic treatment with factor VIII (P less than .05).
Data source: A multicenter laboratory study.
Disclosures: Ms. Hansen had no relevant financial disclosures.
VIDEO: Novel microcapsules show promise in hemophilia A with inhibitory antibodies
SAN DIEGO – Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in models of hemophilia A with inhibitory antibodies, Caroline E. Hansen reported at the annual meeting of the American Society of Hematology.
“This is a completely new paradigm that uses platelet biomechanics to target and deliver a drug,” said Ms. Hansen of Georgia Institute of Technology, Atlanta.
The microcapsules are designed to mechanically shield factor VIII from the immune system. When they reached a modeled site of vascular injury, they contracted and released factor VIII. Initial work showed that this approach triggered significantly more fibrin production in a developing clot than did systemic infusions of factor VIII.
Ms. Hansen had no disclosures. She discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in models of hemophilia A with inhibitory antibodies, Caroline E. Hansen reported at the annual meeting of the American Society of Hematology.
“This is a completely new paradigm that uses platelet biomechanics to target and deliver a drug,” said Ms. Hansen of Georgia Institute of Technology, Atlanta.
The microcapsules are designed to mechanically shield factor VIII from the immune system. When they reached a modeled site of vascular injury, they contracted and released factor VIII. Initial work showed that this approach triggered significantly more fibrin production in a developing clot than did systemic infusions of factor VIII.
Ms. Hansen had no disclosures. She discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in models of hemophilia A with inhibitory antibodies, Caroline E. Hansen reported at the annual meeting of the American Society of Hematology.
“This is a completely new paradigm that uses platelet biomechanics to target and deliver a drug,” said Ms. Hansen of Georgia Institute of Technology, Atlanta.
The microcapsules are designed to mechanically shield factor VIII from the immune system. When they reached a modeled site of vascular injury, they contracted and released factor VIII. Initial work showed that this approach triggered significantly more fibrin production in a developing clot than did systemic infusions of factor VIII.
Ms. Hansen had no disclosures. She discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
Key clinical point: Novel microcapsules loaded with factor VIII outperformed systemic factor VIII infusions in an in vitro model of hemophilia A with inhibitory antibodies.
Major finding: In an in vitro model, the microcapsules triggered 2.7 times more fibrin production than systemic treatment with factor VIII (P less than .05).
Data source: A multicenter laboratory study.
Disclosures: Ms. Hansen had no relevant financial disclosures.
Phase II trial: Drug reduces sickle cell ‘pain crises’
An industry-funded phase II trial has shown that high doses of the experimental drug crizanlizumab significantly reduced the number of dangerous “pain crises” in subjects with sickle cell disease.
The median per-year rate of pain crises was 45.3% lower among those who took the high dose of crizanlizumab, compared with the placebo group (P = .01) More than a third of the subjects who took the high dose reported no pain crises during the treatment phase, more than double the rate among the placebo group.
The trial findings were released at the annual meeting of the American Society of Hematology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1611770).
The American Society of Hematology estimates that 70,000-100,000 people in the United States have sickle cell anemia and some patients are treated with hydroxyurea (Hydrea) are available. According to background material provided in the trial report, however, hydroxyurea has limited value, and some patients still face the prospect of pain crises which can lead to end-organ damage, and early death.
The SUSTAIN trial focuses on pain crises, also known as vaso-occlusive and sickle cell crises, which can occur without warning when sickle cells block blood flow and decrease oxygen delivery.
Researchers led by Kenneth I. Ataga, MB, of the University of North Carolina, Chapel Hill, recruited 198 subjects who had sickle cell disease and who had experienced 2-10 pain crises related to their condition over the past year. They randomly assigned 67 subjects to receive a low 2.5-mg/kg dose of crizanlizumab (also known as SelG1), 66 to a high 5.0-mg/kg dose, and 65 to a placebo. Crizanlizumab is an antibody against the molecule P-selectin, whose up-regulation in certain cells and platelets is thought to contribute to vaso-occlusion and sickle cell pain crises.
All the doses were administered intravenously 14 times over a year at sites in Brazil, the United States, and Jamaica. Risk groups for sickle cell include people of African and South American descent, among groups.
The first two doses were loading doses given at 2-week intervals, and the rest were given at 4-week intervals.
Subjects were aged 16-63 years; the median age was 29 for the two crizanlizumab groups and 26 for the placebo group. The percentage of black subjects ranged from 90% to 94% in each group, and the percentage of female subjects ranged from 52% to 58%.
Some subjects, but not all, were taking hydroxyurea. If they were taking the drug, they needed to have been on it for at least 6 months prior to the trial, and at least the last 3 months at a steady dose. Those who didn’t take hydroxyurea weren’t allowed to start taking it.
The researchers found that the median number of pain crises per year was 1.63 in the high-dose group, 2.01 in the low-dose group, and 2.98 in the placebo group. That translates to a 45.3% lower rate for the high-dose group than placebo (P = .01) and a 32.6% lower rate for low-dose than placebo (P = .18).
A total of 36% of the subjects in the high-dose group had no pain crises during the treatment phase, compared with 18% and 17% in the low-dose and placebo groups, respectively.
In a per-protocol analysis of 125 subjects, the researchers found similar numbers for median pain crises and no pain crises with one exception: The rate of annual pain crises was only 8.3% lower for the low-dose group than the placebo (P = .13).
Overall, the researchers wrote, the rates of adverse and serious adverse events were “similar” among all the subjects regardless of their randomized group.
Five patients died during the trial: two from the high dose group, one in the low dose group, and two in the placebo group. Among serious adverse events, pyrexia and pneumonia occurred more frequently in at least one of the crizanlizumab groups than in the placebo group, but their levels were low at zero to three cases of each event in the three groups.
The researchers noted that they didn’t detect any antibody response against crizanlizumab. However, “longer follow-up and monitoring are necessary to ensure that late neutralizing antibodies do not emerge that might limit the ability to administer crizanlizumab on a long-term basis.”
The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the Food and Drug Administration’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.
An industry-funded phase II trial has shown that high doses of the experimental drug crizanlizumab significantly reduced the number of dangerous “pain crises” in subjects with sickle cell disease.
The median per-year rate of pain crises was 45.3% lower among those who took the high dose of crizanlizumab, compared with the placebo group (P = .01) More than a third of the subjects who took the high dose reported no pain crises during the treatment phase, more than double the rate among the placebo group.
The trial findings were released at the annual meeting of the American Society of Hematology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1611770).
The American Society of Hematology estimates that 70,000-100,000 people in the United States have sickle cell anemia and some patients are treated with hydroxyurea (Hydrea) are available. According to background material provided in the trial report, however, hydroxyurea has limited value, and some patients still face the prospect of pain crises which can lead to end-organ damage, and early death.
The SUSTAIN trial focuses on pain crises, also known as vaso-occlusive and sickle cell crises, which can occur without warning when sickle cells block blood flow and decrease oxygen delivery.
Researchers led by Kenneth I. Ataga, MB, of the University of North Carolina, Chapel Hill, recruited 198 subjects who had sickle cell disease and who had experienced 2-10 pain crises related to their condition over the past year. They randomly assigned 67 subjects to receive a low 2.5-mg/kg dose of crizanlizumab (also known as SelG1), 66 to a high 5.0-mg/kg dose, and 65 to a placebo. Crizanlizumab is an antibody against the molecule P-selectin, whose up-regulation in certain cells and platelets is thought to contribute to vaso-occlusion and sickle cell pain crises.
All the doses were administered intravenously 14 times over a year at sites in Brazil, the United States, and Jamaica. Risk groups for sickle cell include people of African and South American descent, among groups.
The first two doses were loading doses given at 2-week intervals, and the rest were given at 4-week intervals.
Subjects were aged 16-63 years; the median age was 29 for the two crizanlizumab groups and 26 for the placebo group. The percentage of black subjects ranged from 90% to 94% in each group, and the percentage of female subjects ranged from 52% to 58%.
Some subjects, but not all, were taking hydroxyurea. If they were taking the drug, they needed to have been on it for at least 6 months prior to the trial, and at least the last 3 months at a steady dose. Those who didn’t take hydroxyurea weren’t allowed to start taking it.
The researchers found that the median number of pain crises per year was 1.63 in the high-dose group, 2.01 in the low-dose group, and 2.98 in the placebo group. That translates to a 45.3% lower rate for the high-dose group than placebo (P = .01) and a 32.6% lower rate for low-dose than placebo (P = .18).
A total of 36% of the subjects in the high-dose group had no pain crises during the treatment phase, compared with 18% and 17% in the low-dose and placebo groups, respectively.
In a per-protocol analysis of 125 subjects, the researchers found similar numbers for median pain crises and no pain crises with one exception: The rate of annual pain crises was only 8.3% lower for the low-dose group than the placebo (P = .13).
Overall, the researchers wrote, the rates of adverse and serious adverse events were “similar” among all the subjects regardless of their randomized group.
Five patients died during the trial: two from the high dose group, one in the low dose group, and two in the placebo group. Among serious adverse events, pyrexia and pneumonia occurred more frequently in at least one of the crizanlizumab groups than in the placebo group, but their levels were low at zero to three cases of each event in the three groups.
The researchers noted that they didn’t detect any antibody response against crizanlizumab. However, “longer follow-up and monitoring are necessary to ensure that late neutralizing antibodies do not emerge that might limit the ability to administer crizanlizumab on a long-term basis.”
The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the Food and Drug Administration’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.
An industry-funded phase II trial has shown that high doses of the experimental drug crizanlizumab significantly reduced the number of dangerous “pain crises” in subjects with sickle cell disease.
The median per-year rate of pain crises was 45.3% lower among those who took the high dose of crizanlizumab, compared with the placebo group (P = .01) More than a third of the subjects who took the high dose reported no pain crises during the treatment phase, more than double the rate among the placebo group.
The trial findings were released at the annual meeting of the American Society of Hematology and published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1611770).
The American Society of Hematology estimates that 70,000-100,000 people in the United States have sickle cell anemia and some patients are treated with hydroxyurea (Hydrea) are available. According to background material provided in the trial report, however, hydroxyurea has limited value, and some patients still face the prospect of pain crises which can lead to end-organ damage, and early death.
The SUSTAIN trial focuses on pain crises, also known as vaso-occlusive and sickle cell crises, which can occur without warning when sickle cells block blood flow and decrease oxygen delivery.
Researchers led by Kenneth I. Ataga, MB, of the University of North Carolina, Chapel Hill, recruited 198 subjects who had sickle cell disease and who had experienced 2-10 pain crises related to their condition over the past year. They randomly assigned 67 subjects to receive a low 2.5-mg/kg dose of crizanlizumab (also known as SelG1), 66 to a high 5.0-mg/kg dose, and 65 to a placebo. Crizanlizumab is an antibody against the molecule P-selectin, whose up-regulation in certain cells and platelets is thought to contribute to vaso-occlusion and sickle cell pain crises.
All the doses were administered intravenously 14 times over a year at sites in Brazil, the United States, and Jamaica. Risk groups for sickle cell include people of African and South American descent, among groups.
The first two doses were loading doses given at 2-week intervals, and the rest were given at 4-week intervals.
Subjects were aged 16-63 years; the median age was 29 for the two crizanlizumab groups and 26 for the placebo group. The percentage of black subjects ranged from 90% to 94% in each group, and the percentage of female subjects ranged from 52% to 58%.
Some subjects, but not all, were taking hydroxyurea. If they were taking the drug, they needed to have been on it for at least 6 months prior to the trial, and at least the last 3 months at a steady dose. Those who didn’t take hydroxyurea weren’t allowed to start taking it.
The researchers found that the median number of pain crises per year was 1.63 in the high-dose group, 2.01 in the low-dose group, and 2.98 in the placebo group. That translates to a 45.3% lower rate for the high-dose group than placebo (P = .01) and a 32.6% lower rate for low-dose than placebo (P = .18).
A total of 36% of the subjects in the high-dose group had no pain crises during the treatment phase, compared with 18% and 17% in the low-dose and placebo groups, respectively.
In a per-protocol analysis of 125 subjects, the researchers found similar numbers for median pain crises and no pain crises with one exception: The rate of annual pain crises was only 8.3% lower for the low-dose group than the placebo (P = .13).
Overall, the researchers wrote, the rates of adverse and serious adverse events were “similar” among all the subjects regardless of their randomized group.
Five patients died during the trial: two from the high dose group, one in the low dose group, and two in the placebo group. Among serious adverse events, pyrexia and pneumonia occurred more frequently in at least one of the crizanlizumab groups than in the placebo group, but their levels were low at zero to three cases of each event in the three groups.
The researchers noted that they didn’t detect any antibody response against crizanlizumab. However, “longer follow-up and monitoring are necessary to ensure that late neutralizing antibodies do not emerge that might limit the ability to administer crizanlizumab on a long-term basis.”
The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the Food and Drug Administration’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.
FROM ASH 2016
Key clinical point: High-dose crizanlizumab significantly lowers, but does not eliminate, dangerous ‘pain crises’ that strike sickle cell patients.
Major finding: Patients who took high-dose crizanlizumab had a median of 1.63 pain crises a year versus 2.98 for the placebo group. (P = .01)
Data source: A phase II, 12-month, multicenter, double-blind, randomized, placebo-controlled study of 198 patients with sickle cell disease; 129 subjects completed the trial.
Disclosures: The study was funded by Selexys Pharmaceuticals, which received grants from the National Heart, Lung, and Blood Institute and the FDA’s Orphan Products Grant Program. Dr. Ataga reports personal fees from Selexys Pharmaceuticals. The other authors report various disclosures or none. The complete list of disclosures is available at NEJM.org.
SelG1 cut pain crises in sickle cell disease
The humanized antibody SelG1 decreased the frequency of acute pain episodes in people with sickle cell disease, based on results from the multinational, randomized, double-blind, placebo-controlled SUSTAIN study that will be presented at the annual meeting of the American Society of Hematology in San Diego.
In other sickle cell disease research to be presented at the meeting, researchers will be presenting new findings from two studies conducted in Africa. One study examines a team approach to reduce mortality in pregnant women with sickle cell disease in Ghana. The other study, called SPIN, is a safety and feasibility study conducted in advance of a randomized trial in Nigerian children at risk for stroke.
After 1 year, the annual rate of sickle cell–related pain crises resulting in a visit to a medical facility was 1.6 in the group receiving the 5 mg/kg dose, compared with 3 in the placebo group. The 47% difference was statistically significant (P = .01).
Also, time to first pain crisis was a median of 4 months in those who received the 5 mg/kg dose and 1.4 months for those in the placebo group (P = .001).
Infections were not seen increased in either of the groups randomized to SelG1, and no treatment-related deaths occurred during the course of the study. The first-in-class agent “appears to be safe and well tolerated,” as well as effective in reducing pain episodes, Dr. Ataga and his colleagues wrote in their abstract.
In the Nigerian trial, led by Najibah Aliyu Galadanci, MD, MPH, of Bayero University in Kano, Nigeria, the goal was to determine whether families of children with sickle cell disease and transcranial Doppler measurements indicative of increased risk for stroke could be recruited and retained in a large clinical trial, and whether they could adhere to the medication regimen. The trial also obtained preliminary evidence for hydroxyurea’s safety in this clinical setting, where transfusion therapy is not an option for most children.
Dr. Galadanci and her colleagues approached 375 families for transcranial Doppler screening, and 90% accepted. Among families of children found to have elevated measures of risk on transcranial Doppler, 92% participated in the study and received a moderate dose of hydroxyurea (20 mg/kg) for 2 years. A comparison group included 210 children without elevated measures on transcranial Doppler. These children underwent regular monitoring but were not offered medication unless transcranial Doppler measures were found to be elevated.
Study adherence was exceptionally high: the families missed no monthly research visits, and no participants in the active treatment group dropped out voluntarily.
Also, at 2 years, the children treated with hydroxyurea did not have evidence of excessive toxicity, compared with the children who did not receive the drug. “Our results provide strong preliminary evidence supporting the current multicenter randomized controlled trial comparing hydroxyurea therapy (20 mg/kg per day vs. 10 mg/kg per day) for preventing primary strokes in children with sickle cell anemia living in Nigeria,” Dr. Galadanci and her colleagues wrote in their abstract.
In the third study, a multidisciplinary team decreased mortality in pregnant women who had sickle cell disease and lived in low and middle income settings, according to Eugenia Vicky Naa Kwarley Asare, MD, of the Ghana Institute of Clinical Genetics and the Korle-Bu Teaching Hospital in Accra.
In a prospective trial in Ghana, where maternal mortality among women with sickle cell disease is estimated to be 8,300 per 100,000 live births, compared with 690 for women without sickle cell disease, Dr. Asare and her colleagues’ multidisciplinary team included obstetricians, hematologists, pulmonologists, and nurses, and the planned intervention protocols included a number of changes to make management more consistent and intensive. A total of 154 pregnancies were evaluated before the intervention, and 91 after. Median gestational age was 24 weeks at enrollment, and median maternal age was 29 years for both pre- and post-intervention cohorts.
Maternal mortality before the intervention was 9.7% (15 of 154) and after the intervention was 1.1% (1 of 91) of total deliveries.
Dr. Ataga’s study was sponsored by Selexys Pharmaceuticals, the drug’s manufacturer, and included coinvestigators who are employees of Selexys Pharmaceuticals or who disclosed relationships with other drug manufacturers. Dr. Galadanci’s and Dr. Asare’s groups disclosed no conflicts of interest.
The humanized antibody SelG1 decreased the frequency of acute pain episodes in people with sickle cell disease, based on results from the multinational, randomized, double-blind, placebo-controlled SUSTAIN study that will be presented at the annual meeting of the American Society of Hematology in San Diego.
In other sickle cell disease research to be presented at the meeting, researchers will be presenting new findings from two studies conducted in Africa. One study examines a team approach to reduce mortality in pregnant women with sickle cell disease in Ghana. The other study, called SPIN, is a safety and feasibility study conducted in advance of a randomized trial in Nigerian children at risk for stroke.
After 1 year, the annual rate of sickle cell–related pain crises resulting in a visit to a medical facility was 1.6 in the group receiving the 5 mg/kg dose, compared with 3 in the placebo group. The 47% difference was statistically significant (P = .01).
Also, time to first pain crisis was a median of 4 months in those who received the 5 mg/kg dose and 1.4 months for those in the placebo group (P = .001).
Infections were not seen increased in either of the groups randomized to SelG1, and no treatment-related deaths occurred during the course of the study. The first-in-class agent “appears to be safe and well tolerated,” as well as effective in reducing pain episodes, Dr. Ataga and his colleagues wrote in their abstract.
In the Nigerian trial, led by Najibah Aliyu Galadanci, MD, MPH, of Bayero University in Kano, Nigeria, the goal was to determine whether families of children with sickle cell disease and transcranial Doppler measurements indicative of increased risk for stroke could be recruited and retained in a large clinical trial, and whether they could adhere to the medication regimen. The trial also obtained preliminary evidence for hydroxyurea’s safety in this clinical setting, where transfusion therapy is not an option for most children.
Dr. Galadanci and her colleagues approached 375 families for transcranial Doppler screening, and 90% accepted. Among families of children found to have elevated measures of risk on transcranial Doppler, 92% participated in the study and received a moderate dose of hydroxyurea (20 mg/kg) for 2 years. A comparison group included 210 children without elevated measures on transcranial Doppler. These children underwent regular monitoring but were not offered medication unless transcranial Doppler measures were found to be elevated.
Study adherence was exceptionally high: the families missed no monthly research visits, and no participants in the active treatment group dropped out voluntarily.
Also, at 2 years, the children treated with hydroxyurea did not have evidence of excessive toxicity, compared with the children who did not receive the drug. “Our results provide strong preliminary evidence supporting the current multicenter randomized controlled trial comparing hydroxyurea therapy (20 mg/kg per day vs. 10 mg/kg per day) for preventing primary strokes in children with sickle cell anemia living in Nigeria,” Dr. Galadanci and her colleagues wrote in their abstract.
In the third study, a multidisciplinary team decreased mortality in pregnant women who had sickle cell disease and lived in low and middle income settings, according to Eugenia Vicky Naa Kwarley Asare, MD, of the Ghana Institute of Clinical Genetics and the Korle-Bu Teaching Hospital in Accra.
In a prospective trial in Ghana, where maternal mortality among women with sickle cell disease is estimated to be 8,300 per 100,000 live births, compared with 690 for women without sickle cell disease, Dr. Asare and her colleagues’ multidisciplinary team included obstetricians, hematologists, pulmonologists, and nurses, and the planned intervention protocols included a number of changes to make management more consistent and intensive. A total of 154 pregnancies were evaluated before the intervention, and 91 after. Median gestational age was 24 weeks at enrollment, and median maternal age was 29 years for both pre- and post-intervention cohorts.
Maternal mortality before the intervention was 9.7% (15 of 154) and after the intervention was 1.1% (1 of 91) of total deliveries.
Dr. Ataga’s study was sponsored by Selexys Pharmaceuticals, the drug’s manufacturer, and included coinvestigators who are employees of Selexys Pharmaceuticals or who disclosed relationships with other drug manufacturers. Dr. Galadanci’s and Dr. Asare’s groups disclosed no conflicts of interest.
The humanized antibody SelG1 decreased the frequency of acute pain episodes in people with sickle cell disease, based on results from the multinational, randomized, double-blind, placebo-controlled SUSTAIN study that will be presented at the annual meeting of the American Society of Hematology in San Diego.
In other sickle cell disease research to be presented at the meeting, researchers will be presenting new findings from two studies conducted in Africa. One study examines a team approach to reduce mortality in pregnant women with sickle cell disease in Ghana. The other study, called SPIN, is a safety and feasibility study conducted in advance of a randomized trial in Nigerian children at risk for stroke.
After 1 year, the annual rate of sickle cell–related pain crises resulting in a visit to a medical facility was 1.6 in the group receiving the 5 mg/kg dose, compared with 3 in the placebo group. The 47% difference was statistically significant (P = .01).
Also, time to first pain crisis was a median of 4 months in those who received the 5 mg/kg dose and 1.4 months for those in the placebo group (P = .001).
Infections were not seen increased in either of the groups randomized to SelG1, and no treatment-related deaths occurred during the course of the study. The first-in-class agent “appears to be safe and well tolerated,” as well as effective in reducing pain episodes, Dr. Ataga and his colleagues wrote in their abstract.
In the Nigerian trial, led by Najibah Aliyu Galadanci, MD, MPH, of Bayero University in Kano, Nigeria, the goal was to determine whether families of children with sickle cell disease and transcranial Doppler measurements indicative of increased risk for stroke could be recruited and retained in a large clinical trial, and whether they could adhere to the medication regimen. The trial also obtained preliminary evidence for hydroxyurea’s safety in this clinical setting, where transfusion therapy is not an option for most children.
Dr. Galadanci and her colleagues approached 375 families for transcranial Doppler screening, and 90% accepted. Among families of children found to have elevated measures of risk on transcranial Doppler, 92% participated in the study and received a moderate dose of hydroxyurea (20 mg/kg) for 2 years. A comparison group included 210 children without elevated measures on transcranial Doppler. These children underwent regular monitoring but were not offered medication unless transcranial Doppler measures were found to be elevated.
Study adherence was exceptionally high: the families missed no monthly research visits, and no participants in the active treatment group dropped out voluntarily.
Also, at 2 years, the children treated with hydroxyurea did not have evidence of excessive toxicity, compared with the children who did not receive the drug. “Our results provide strong preliminary evidence supporting the current multicenter randomized controlled trial comparing hydroxyurea therapy (20 mg/kg per day vs. 10 mg/kg per day) for preventing primary strokes in children with sickle cell anemia living in Nigeria,” Dr. Galadanci and her colleagues wrote in their abstract.
In the third study, a multidisciplinary team decreased mortality in pregnant women who had sickle cell disease and lived in low and middle income settings, according to Eugenia Vicky Naa Kwarley Asare, MD, of the Ghana Institute of Clinical Genetics and the Korle-Bu Teaching Hospital in Accra.
In a prospective trial in Ghana, where maternal mortality among women with sickle cell disease is estimated to be 8,300 per 100,000 live births, compared with 690 for women without sickle cell disease, Dr. Asare and her colleagues’ multidisciplinary team included obstetricians, hematologists, pulmonologists, and nurses, and the planned intervention protocols included a number of changes to make management more consistent and intensive. A total of 154 pregnancies were evaluated before the intervention, and 91 after. Median gestational age was 24 weeks at enrollment, and median maternal age was 29 years for both pre- and post-intervention cohorts.
Maternal mortality before the intervention was 9.7% (15 of 154) and after the intervention was 1.1% (1 of 91) of total deliveries.
Dr. Ataga’s study was sponsored by Selexys Pharmaceuticals, the drug’s manufacturer, and included coinvestigators who are employees of Selexys Pharmaceuticals or who disclosed relationships with other drug manufacturers. Dr. Galadanci’s and Dr. Asare’s groups disclosed no conflicts of interest.
FROM ASH 2016
Factor VIII microcapsules eyed for eluding neutralizing antibodies
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
[email protected]
On Twitter @maryjodales
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
[email protected]
On Twitter @maryjodales
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
[email protected]
On Twitter @maryjodales
ASH 2016 PREVIEW
Investigational AML drugs boosted remission rates
Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.
In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.
The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.
Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.
For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).
For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).
In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.
Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.
Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.
An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.
The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.
The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.
Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.
[email protected]
On Twitter @maryjodales
Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.
In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.
The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.
Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.
For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).
For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).
In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.
Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.
Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.
An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.
The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.
The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.
Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.
[email protected]
On Twitter @maryjodales
Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.
In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.
The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.
Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.
For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).
For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).
In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.
Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.
Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.
An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.
The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.
The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.
Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.
[email protected]
On Twitter @maryjodales
FROM ASH 2016