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How Abl ‘shape-shifts’ in drug-resistant CML
Researchers say they have determined how the structure of Abl kinase regulates its activity, enabling the enzyme to switch itself on and off.
The team believes these findings will pave the way to new treatment strategies that can overcome drug resistance in chronic myeloid leukemia (CML) and other malignancies.
Charalampos Kalodimos, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Structural & Molecular Biology.
The researchers sought to understand how Abl manages to switch itself on and off by altering its shape. Abl controls this switching through allosteric regulation, in which a part of the molecule distant from its kinase domain somehow inhibits or activates Abl.
“We knew we had these 2 functional states, but we had no idea about the conditions under which Abl switched from one to another,” Dr Kalodimos said.
“We also didn’t understand how external molecules that regulate Abl acted on these 2 states. Nor did we understand how mutations that confer drug resistance affected the states.”
To investigate, the researchers used NMR spectroscopy to view Abl’s structure and watch the kinase change. The team explored how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it.
The research revealed that, in its shape-shifting, Abl was precisely balanced between its inhibition and activation states.
“We saw this very fast ‘breathing’ motion of several thousand times a second, in which the molecule goes on and off, on and off,” Dr Kalodimos said. “This motion is important because it allows other molecules that regulate Abl to adjust its activity one way or the other in a graded manner—like turning a rheostat up or down.”
Such regulation would involve pushing the Abl molecule toward either the inhibited or activated state, Dr Kalodimos said.
Newfound activator region
The researchers also discovered new details about how Abl’s structure affects its activation state. For example, the team’s experiments revealed a previously unknown activator region within Abl.
The researchers noted that the Abl regulatory module consists of 5 regions:
- An unstructured N-terminal region called the cap (residues 1–80)
- The SH3 domain (residues 85–138)
- A short linker called the connectorSH3/2 (residues 139–152), which links the SH3 and SH2 domains
- The SH2 domain (residues 153–237)
- A linker (linkerSH2–KD; residues 238–250) that connects SH2 to the kinase domain (residues 255–534).
The previously unknown activator region the researchers identified is part of the cap region comprising residues 14 to 20 (capPxxP), which carries a PxxP sequence motif, a preferred binding site of the SH3 domain.
The team found that capPxxP is an SH3-binding site that can compete with and displace the linkerSH2–KD from the SH3 domain, thereby destabilizing the inhibiting state.
The researchers said they believe the recently reported A19V drug-resistance mutation exerts its function by promoting the activated state of Abl by means of capPxxP.
Implications for treatment
The researchers also analyzed mutations in Bcr-Abl that allow it to become resistant to imatinib. The drug has proven effective in treating CML by plugging into the kinase domain of the over-activated Abl enzyme and shutting it down. However, in many patients, a mutation in the gene that produces Abl renders it drug-resistant.
While many of the mutations block imatinib from plugging into the kinase domain, others appear to interfere with the allosteric regulation. In effect, they may “warp” the enzyme to keep it activated.
In analyzing the structure of these allosteric mutants, Dr Kalodimos and his colleagues discovered the mutants altered Abl’s shape to activate it and did not interfere with how imatinib plugs into the kinase domain.
This finding points the way to new treatments to overcome such resistance, according to Dr Kalodimos.
“There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,” he said. “These could be combined with [imatinib] to overcome allosteric mutations to shift Abl into an inhibited state.”
Dr Kalodimos said that treatment strategy could also be applied to other forms of leukemia that have uncontrolled Bcr-Abl activity. And this new basic understanding of Abl regulation will yield insight into similar enzymes in which allosteric regulation controls a kinase domain. 
Researchers say they have determined how the structure of Abl kinase regulates its activity, enabling the enzyme to switch itself on and off.
The team believes these findings will pave the way to new treatment strategies that can overcome drug resistance in chronic myeloid leukemia (CML) and other malignancies.
Charalampos Kalodimos, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Structural & Molecular Biology.
The researchers sought to understand how Abl manages to switch itself on and off by altering its shape. Abl controls this switching through allosteric regulation, in which a part of the molecule distant from its kinase domain somehow inhibits or activates Abl.
“We knew we had these 2 functional states, but we had no idea about the conditions under which Abl switched from one to another,” Dr Kalodimos said.
“We also didn’t understand how external molecules that regulate Abl acted on these 2 states. Nor did we understand how mutations that confer drug resistance affected the states.”
To investigate, the researchers used NMR spectroscopy to view Abl’s structure and watch the kinase change. The team explored how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it.
The research revealed that, in its shape-shifting, Abl was precisely balanced between its inhibition and activation states.
“We saw this very fast ‘breathing’ motion of several thousand times a second, in which the molecule goes on and off, on and off,” Dr Kalodimos said. “This motion is important because it allows other molecules that regulate Abl to adjust its activity one way or the other in a graded manner—like turning a rheostat up or down.”
Such regulation would involve pushing the Abl molecule toward either the inhibited or activated state, Dr Kalodimos said.
Newfound activator region
The researchers also discovered new details about how Abl’s structure affects its activation state. For example, the team’s experiments revealed a previously unknown activator region within Abl.
The researchers noted that the Abl regulatory module consists of 5 regions:
- An unstructured N-terminal region called the cap (residues 1–80)
- The SH3 domain (residues 85–138)
- A short linker called the connectorSH3/2 (residues 139–152), which links the SH3 and SH2 domains
- The SH2 domain (residues 153–237)
- A linker (linkerSH2–KD; residues 238–250) that connects SH2 to the kinase domain (residues 255–534).
The previously unknown activator region the researchers identified is part of the cap region comprising residues 14 to 20 (capPxxP), which carries a PxxP sequence motif, a preferred binding site of the SH3 domain.
The team found that capPxxP is an SH3-binding site that can compete with and displace the linkerSH2–KD from the SH3 domain, thereby destabilizing the inhibiting state.
The researchers said they believe the recently reported A19V drug-resistance mutation exerts its function by promoting the activated state of Abl by means of capPxxP.
Implications for treatment
The researchers also analyzed mutations in Bcr-Abl that allow it to become resistant to imatinib. The drug has proven effective in treating CML by plugging into the kinase domain of the over-activated Abl enzyme and shutting it down. However, in many patients, a mutation in the gene that produces Abl renders it drug-resistant.
While many of the mutations block imatinib from plugging into the kinase domain, others appear to interfere with the allosteric regulation. In effect, they may “warp” the enzyme to keep it activated.
In analyzing the structure of these allosteric mutants, Dr Kalodimos and his colleagues discovered the mutants altered Abl’s shape to activate it and did not interfere with how imatinib plugs into the kinase domain.
This finding points the way to new treatments to overcome such resistance, according to Dr Kalodimos.
“There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,” he said. “These could be combined with [imatinib] to overcome allosteric mutations to shift Abl into an inhibited state.”
Dr Kalodimos said that treatment strategy could also be applied to other forms of leukemia that have uncontrolled Bcr-Abl activity. And this new basic understanding of Abl regulation will yield insight into similar enzymes in which allosteric regulation controls a kinase domain.
Researchers say they have determined how the structure of Abl kinase regulates its activity, enabling the enzyme to switch itself on and off.
The team believes these findings will pave the way to new treatment strategies that can overcome drug resistance in chronic myeloid leukemia (CML) and other malignancies.
Charalampos Kalodimos, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Structural & Molecular Biology.
The researchers sought to understand how Abl manages to switch itself on and off by altering its shape. Abl controls this switching through allosteric regulation, in which a part of the molecule distant from its kinase domain somehow inhibits or activates Abl.
“We knew we had these 2 functional states, but we had no idea about the conditions under which Abl switched from one to another,” Dr Kalodimos said.
“We also didn’t understand how external molecules that regulate Abl acted on these 2 states. Nor did we understand how mutations that confer drug resistance affected the states.”
To investigate, the researchers used NMR spectroscopy to view Abl’s structure and watch the kinase change. The team explored how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it.
The research revealed that, in its shape-shifting, Abl was precisely balanced between its inhibition and activation states.
“We saw this very fast ‘breathing’ motion of several thousand times a second, in which the molecule goes on and off, on and off,” Dr Kalodimos said. “This motion is important because it allows other molecules that regulate Abl to adjust its activity one way or the other in a graded manner—like turning a rheostat up or down.”
Such regulation would involve pushing the Abl molecule toward either the inhibited or activated state, Dr Kalodimos said.
Newfound activator region
The researchers also discovered new details about how Abl’s structure affects its activation state. For example, the team’s experiments revealed a previously unknown activator region within Abl.
The researchers noted that the Abl regulatory module consists of 5 regions:
- An unstructured N-terminal region called the cap (residues 1–80)
- The SH3 domain (residues 85–138)
- A short linker called the connectorSH3/2 (residues 139–152), which links the SH3 and SH2 domains
- The SH2 domain (residues 153–237)
- A linker (linkerSH2–KD; residues 238–250) that connects SH2 to the kinase domain (residues 255–534).
The previously unknown activator region the researchers identified is part of the cap region comprising residues 14 to 20 (capPxxP), which carries a PxxP sequence motif, a preferred binding site of the SH3 domain.
The team found that capPxxP is an SH3-binding site that can compete with and displace the linkerSH2–KD from the SH3 domain, thereby destabilizing the inhibiting state.
The researchers said they believe the recently reported A19V drug-resistance mutation exerts its function by promoting the activated state of Abl by means of capPxxP.
Implications for treatment
The researchers also analyzed mutations in Bcr-Abl that allow it to become resistant to imatinib. The drug has proven effective in treating CML by plugging into the kinase domain of the over-activated Abl enzyme and shutting it down. However, in many patients, a mutation in the gene that produces Abl renders it drug-resistant.
While many of the mutations block imatinib from plugging into the kinase domain, others appear to interfere with the allosteric regulation. In effect, they may “warp” the enzyme to keep it activated.
In analyzing the structure of these allosteric mutants, Dr Kalodimos and his colleagues discovered the mutants altered Abl’s shape to activate it and did not interfere with how imatinib plugs into the kinase domain.
This finding points the way to new treatments to overcome such resistance, according to Dr Kalodimos.
“There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,” he said. “These could be combined with [imatinib] to overcome allosteric mutations to shift Abl into an inhibited state.”
Dr Kalodimos said that treatment strategy could also be applied to other forms of leukemia that have uncontrolled Bcr-Abl activity. And this new basic understanding of Abl regulation will yield insight into similar enzymes in which allosteric regulation controls a kinase domain.
Fostamatinib elicits responses in AIHA
The oral SYK inhibitor fostamatinib can produce responses in patients with warm antibody autoimmune hemolytic anemia (AIHA), according to Rigel Pharmaceuticals, Inc.
The company reported topline results from the first stage of the phase 2 SOAR study, which showed that fostamatinib produced a 35% response rate.
A response was defined as achieving a hemoglobin level of greater than 10 g/dL and at least a 2 g/dL increase from baseline.
“Many patients with AIHA suffer from severe, debilitating disease that negatively affects their quality of life,” said David J. Kuter, MD, the director for the Center of Hematology at Massachusetts General Hospital in Boston and the lead investigator of the SOAR study.
“There are no FDA-approved medications for the treatment of AIHA, which means that those living with the condition are in need of new and effective therapeutic options.”
In the SOAR study, Dr Kuter and his colleagues are evaluating fostamatinib in patients with warm antibody AIHA who previously received at least 1 treatment but did not have a meaningful benefit and are still anemic.
The study utilizes an open-label, Simon 2-stage design to evaluate fostamatinib given at 150 mg twice daily.
Stage 1 has enrolled 17 patients who have had at least 1 post-baseline hemoglobin measure.
Four of these patients responded to fostamatinib during the 12-week evaluation period, and an additional 2 patients met response criteria in the extension study after 12 weeks of dosing.
So the overall response rate was 35% (6/17), although Rigel Pharmaceuticals said these data are preliminary and require further verification.
Two patients withdrew from the study early due to non-safety-related reasons and will be replaced per the study protocol.
According to Rigel Pharmaceuticals, the treatment-emergent adverse events (AEs) in this trial were consistent with the prior clinical experience with fostamatinib.
Treatment-emergent AEs—which included diarrhea, elevated liver function tests, and hypertension—were manageable and mostly mild or moderate in nature.
There were 2 deaths reported during the trial. Both were due to non-treatment-related serious AEs, according to investigators. One patient had skin necrosis and infection. The other was an elderly patient who had pneumonia and was immunosuppressed due to prior chronic lymphocytic leukemia and steroid use.
A third patient experienced a non-treatment-related serious AE but recovered and continued on treatment.
Rigel Pharmaceuticals said a comprehensive analysis of the data will continue and will be presented at a future scientific conference.
The company also intends to begin enrollment for stage 2 of this study, in which 20 patients will be enrolled under the same protocol.
The oral SYK inhibitor fostamatinib can produce responses in patients with warm antibody autoimmune hemolytic anemia (AIHA), according to Rigel Pharmaceuticals, Inc.
The company reported topline results from the first stage of the phase 2 SOAR study, which showed that fostamatinib produced a 35% response rate.
A response was defined as achieving a hemoglobin level of greater than 10 g/dL and at least a 2 g/dL increase from baseline.
“Many patients with AIHA suffer from severe, debilitating disease that negatively affects their quality of life,” said David J. Kuter, MD, the director for the Center of Hematology at Massachusetts General Hospital in Boston and the lead investigator of the SOAR study.
“There are no FDA-approved medications for the treatment of AIHA, which means that those living with the condition are in need of new and effective therapeutic options.”
In the SOAR study, Dr Kuter and his colleagues are evaluating fostamatinib in patients with warm antibody AIHA who previously received at least 1 treatment but did not have a meaningful benefit and are still anemic.
The study utilizes an open-label, Simon 2-stage design to evaluate fostamatinib given at 150 mg twice daily.
Stage 1 has enrolled 17 patients who have had at least 1 post-baseline hemoglobin measure.
Four of these patients responded to fostamatinib during the 12-week evaluation period, and an additional 2 patients met response criteria in the extension study after 12 weeks of dosing.
So the overall response rate was 35% (6/17), although Rigel Pharmaceuticals said these data are preliminary and require further verification.
Two patients withdrew from the study early due to non-safety-related reasons and will be replaced per the study protocol.
According to Rigel Pharmaceuticals, the treatment-emergent adverse events (AEs) in this trial were consistent with the prior clinical experience with fostamatinib.
Treatment-emergent AEs—which included diarrhea, elevated liver function tests, and hypertension—were manageable and mostly mild or moderate in nature.
There were 2 deaths reported during the trial. Both were due to non-treatment-related serious AEs, according to investigators. One patient had skin necrosis and infection. The other was an elderly patient who had pneumonia and was immunosuppressed due to prior chronic lymphocytic leukemia and steroid use.
A third patient experienced a non-treatment-related serious AE but recovered and continued on treatment.
Rigel Pharmaceuticals said a comprehensive analysis of the data will continue and will be presented at a future scientific conference.
The company also intends to begin enrollment for stage 2 of this study, in which 20 patients will be enrolled under the same protocol.
The oral SYK inhibitor fostamatinib can produce responses in patients with warm antibody autoimmune hemolytic anemia (AIHA), according to Rigel Pharmaceuticals, Inc.
The company reported topline results from the first stage of the phase 2 SOAR study, which showed that fostamatinib produced a 35% response rate.
A response was defined as achieving a hemoglobin level of greater than 10 g/dL and at least a 2 g/dL increase from baseline.
“Many patients with AIHA suffer from severe, debilitating disease that negatively affects their quality of life,” said David J. Kuter, MD, the director for the Center of Hematology at Massachusetts General Hospital in Boston and the lead investigator of the SOAR study.
“There are no FDA-approved medications for the treatment of AIHA, which means that those living with the condition are in need of new and effective therapeutic options.”
In the SOAR study, Dr Kuter and his colleagues are evaluating fostamatinib in patients with warm antibody AIHA who previously received at least 1 treatment but did not have a meaningful benefit and are still anemic.
The study utilizes an open-label, Simon 2-stage design to evaluate fostamatinib given at 150 mg twice daily.
Stage 1 has enrolled 17 patients who have had at least 1 post-baseline hemoglobin measure.
Four of these patients responded to fostamatinib during the 12-week evaluation period, and an additional 2 patients met response criteria in the extension study after 12 weeks of dosing.
So the overall response rate was 35% (6/17), although Rigel Pharmaceuticals said these data are preliminary and require further verification.
Two patients withdrew from the study early due to non-safety-related reasons and will be replaced per the study protocol.
According to Rigel Pharmaceuticals, the treatment-emergent adverse events (AEs) in this trial were consistent with the prior clinical experience with fostamatinib.
Treatment-emergent AEs—which included diarrhea, elevated liver function tests, and hypertension—were manageable and mostly mild or moderate in nature.
There were 2 deaths reported during the trial. Both were due to non-treatment-related serious AEs, according to investigators. One patient had skin necrosis and infection. The other was an elderly patient who had pneumonia and was immunosuppressed due to prior chronic lymphocytic leukemia and steroid use.
A third patient experienced a non-treatment-related serious AE but recovered and continued on treatment.
Rigel Pharmaceuticals said a comprehensive analysis of the data will continue and will be presented at a future scientific conference.
The company also intends to begin enrollment for stage 2 of this study, in which 20 patients will be enrolled under the same protocol.
Caplacizumab may enhance treatment of aTTP
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A key secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
Drug receives breakthrough designation for HL
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (BV, Adcetris) for use in combination with chemotherapy as frontline treatment of advanced classical Hodgkin lymphoma (HL).
Seattle Genetics and Takeda plan to submit a supplemental biologics license application seeking approval for BV in this indication before the end of this year.
The breakthrough designation is based on positive topline results from the phase 3 ECHELON-1 trial.
Full results from this trial are expected to be presented at the 2017 ASH Annual Meeting in December.
BV is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
BV is currently FDA-approved to treat:
- Classical HL after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
- Classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation.
BV also has accelerated approval from the FDA for the treatment of systemic anaplastic large-cell lymphoma after failure of at least 1 prior multi-agent chemotherapy regimen. This approval is based on overall response rate. Continued approval of BV for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
ECHELON-1 trial
In this phase 3 trial, researchers compared BV in combination with doxorubicin, vinblastine, and dacarbazine to a recognized standard of care chemotherapy regimen in patients with previously untreated, advanced classical HL.
The study enrolled 1334 patients who had a histologically confirmed diagnosis of stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy.
The study’s primary endpoint is modified progression-free survival (PFS) per an independent review facility. Modified PFS is defined as the time to progression, death, or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy.
There was a significant improvement in modified PFS in the BV arm compared to the control arm (hazard ratio=0.770; P=0.035). The 2-year modified PFS rate was 82.1% in the BV arm and 77.2% in the control arm.
An interim analysis of overall survival revealed a trend in favor of the BV arm.
The safety profile of BV plus chemotherapy was consistent with the profile known for the single-agent components of the regimen.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (BV, Adcetris) for use in combination with chemotherapy as frontline treatment of advanced classical Hodgkin lymphoma (HL).
Seattle Genetics and Takeda plan to submit a supplemental biologics license application seeking approval for BV in this indication before the end of this year.
The breakthrough designation is based on positive topline results from the phase 3 ECHELON-1 trial.
Full results from this trial are expected to be presented at the 2017 ASH Annual Meeting in December.
BV is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
BV is currently FDA-approved to treat:
- Classical HL after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
- Classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation.
BV also has accelerated approval from the FDA for the treatment of systemic anaplastic large-cell lymphoma after failure of at least 1 prior multi-agent chemotherapy regimen. This approval is based on overall response rate. Continued approval of BV for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
ECHELON-1 trial
In this phase 3 trial, researchers compared BV in combination with doxorubicin, vinblastine, and dacarbazine to a recognized standard of care chemotherapy regimen in patients with previously untreated, advanced classical HL.
The study enrolled 1334 patients who had a histologically confirmed diagnosis of stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy.
The study’s primary endpoint is modified progression-free survival (PFS) per an independent review facility. Modified PFS is defined as the time to progression, death, or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy.
There was a significant improvement in modified PFS in the BV arm compared to the control arm (hazard ratio=0.770; P=0.035). The 2-year modified PFS rate was 82.1% in the BV arm and 77.2% in the control arm.
An interim analysis of overall survival revealed a trend in favor of the BV arm.
The safety profile of BV plus chemotherapy was consistent with the profile known for the single-agent components of the regimen.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to brentuximab vedotin (BV, Adcetris) for use in combination with chemotherapy as frontline treatment of advanced classical Hodgkin lymphoma (HL).
Seattle Genetics and Takeda plan to submit a supplemental biologics license application seeking approval for BV in this indication before the end of this year.
The breakthrough designation is based on positive topline results from the phase 3 ECHELON-1 trial.
Full results from this trial are expected to be presented at the 2017 ASH Annual Meeting in December.
BV is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
BV is currently FDA-approved to treat:
- Classical HL after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
- Classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation.
BV also has accelerated approval from the FDA for the treatment of systemic anaplastic large-cell lymphoma after failure of at least 1 prior multi-agent chemotherapy regimen. This approval is based on overall response rate. Continued approval of BV for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
ECHELON-1 trial
In this phase 3 trial, researchers compared BV in combination with doxorubicin, vinblastine, and dacarbazine to a recognized standard of care chemotherapy regimen in patients with previously untreated, advanced classical HL.
The study enrolled 1334 patients who had a histologically confirmed diagnosis of stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy.
The study’s primary endpoint is modified progression-free survival (PFS) per an independent review facility. Modified PFS is defined as the time to progression, death, or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy.
There was a significant improvement in modified PFS in the BV arm compared to the control arm (hazard ratio=0.770; P=0.035). The 2-year modified PFS rate was 82.1% in the BV arm and 77.2% in the control arm.
An interim analysis of overall survival revealed a trend in favor of the BV arm.
The safety profile of BV plus chemotherapy was consistent with the profile known for the single-agent components of the regimen.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA grants EUA to Zika testing system
The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for Chembio Diagnostics, Inc.’s DPP® Zika System.
The system includes the DPP Zika IgM Assay, which enables in vitro qualitative detection of human IgM antibodies to Zika virus, and the DPP Micro Reader, which is a portable, hand-held device intended to reduce the risk of human error during test interpretation.
The DPP Zika System provides results in 15 to 20 minutes from 10 µL of blood.
The system is designed to detect Zika virus IgM antibodies in finger-stick whole blood, EDTA venous whole blood, EDTA plasma (each collected alongside a patient-matched serum specimen), or serum (plain or separation gel) specimens.
The EUA for the DPP Zika System does not mean it is FDA cleared or approved.
An EUA allows for the use of unapproved medical products (or unapproved uses of approved medical products) in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the DPP Zika System means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the DPP Zika System is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The DPP Zika System can be used to test individuals who meet the Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (eg, a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, a history of residence in or travel to a geographic region with active Zika transmission at the time of travel or other epidemiological criteria for which Zika virus testing may be indicated).
The DPP Zika System can be used starting 8 days after symptom onset or risk of exposure and for up to 12 weeks after that point.
Where there are reactive results from the DPP Zika IgM Assay, confirmation of the presence of anti-Zika IgM antibodies requires additional testing and/or consideration alongside test results for other patient-matched specimens using the latest CDC testing algorithms for the diagnosis of Zika virus infection.
Development of the DPP Zika System has been funded, in part, with federal funds from the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the US Department of Health and Human Services.
Chembio Diagnostics, Inc. has been awarded a contract for $5.9 million to develop the product and obtain EUA and 510(k) clearance from the FDA, with the potential of $13.2 million in total funding from BARDA if all options are exercised, to advance clinical development of the DPP Zika System and DPP® Zika/Dengue/Chikungunya System.
More information on the DPP Zika System and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for Chembio Diagnostics, Inc.’s DPP® Zika System.
The system includes the DPP Zika IgM Assay, which enables in vitro qualitative detection of human IgM antibodies to Zika virus, and the DPP Micro Reader, which is a portable, hand-held device intended to reduce the risk of human error during test interpretation.
The DPP Zika System provides results in 15 to 20 minutes from 10 µL of blood.
The system is designed to detect Zika virus IgM antibodies in finger-stick whole blood, EDTA venous whole blood, EDTA plasma (each collected alongside a patient-matched serum specimen), or serum (plain or separation gel) specimens.
The EUA for the DPP Zika System does not mean it is FDA cleared or approved.
An EUA allows for the use of unapproved medical products (or unapproved uses of approved medical products) in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the DPP Zika System means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the DPP Zika System is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The DPP Zika System can be used to test individuals who meet the Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (eg, a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, a history of residence in or travel to a geographic region with active Zika transmission at the time of travel or other epidemiological criteria for which Zika virus testing may be indicated).
The DPP Zika System can be used starting 8 days after symptom onset or risk of exposure and for up to 12 weeks after that point.
Where there are reactive results from the DPP Zika IgM Assay, confirmation of the presence of anti-Zika IgM antibodies requires additional testing and/or consideration alongside test results for other patient-matched specimens using the latest CDC testing algorithms for the diagnosis of Zika virus infection.
Development of the DPP Zika System has been funded, in part, with federal funds from the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the US Department of Health and Human Services.
Chembio Diagnostics, Inc. has been awarded a contract for $5.9 million to develop the product and obtain EUA and 510(k) clearance from the FDA, with the potential of $13.2 million in total funding from BARDA if all options are exercised, to advance clinical development of the DPP Zika System and DPP® Zika/Dengue/Chikungunya System.
More information on the DPP Zika System and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for Chembio Diagnostics, Inc.’s DPP® Zika System.
The system includes the DPP Zika IgM Assay, which enables in vitro qualitative detection of human IgM antibodies to Zika virus, and the DPP Micro Reader, which is a portable, hand-held device intended to reduce the risk of human error during test interpretation.
The DPP Zika System provides results in 15 to 20 minutes from 10 µL of blood.
The system is designed to detect Zika virus IgM antibodies in finger-stick whole blood, EDTA venous whole blood, EDTA plasma (each collected alongside a patient-matched serum specimen), or serum (plain or separation gel) specimens.
The EUA for the DPP Zika System does not mean it is FDA cleared or approved.
An EUA allows for the use of unapproved medical products (or unapproved uses of approved medical products) in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the DPP Zika System means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the DPP Zika System is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The DPP Zika System can be used to test individuals who meet the Centers for Disease Control and Prevention (CDC) Zika virus clinical criteria (eg, a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, a history of residence in or travel to a geographic region with active Zika transmission at the time of travel or other epidemiological criteria for which Zika virus testing may be indicated).
The DPP Zika System can be used starting 8 days after symptom onset or risk of exposure and for up to 12 weeks after that point.
Where there are reactive results from the DPP Zika IgM Assay, confirmation of the presence of anti-Zika IgM antibodies requires additional testing and/or consideration alongside test results for other patient-matched specimens using the latest CDC testing algorithms for the diagnosis of Zika virus infection.
Development of the DPP Zika System has been funded, in part, with federal funds from the Biomedical Advanced Research and Development Authority (BARDA) within the Office of the Assistant Secretary for Preparedness and Response in the US Department of Health and Human Services.
Chembio Diagnostics, Inc. has been awarded a contract for $5.9 million to develop the product and obtain EUA and 510(k) clearance from the FDA, with the potential of $13.2 million in total funding from BARDA if all options are exercised, to advance clinical development of the DPP Zika System and DPP® Zika/Dengue/Chikungunya System.
More information on the DPP Zika System and other Zika tests granted EUAs can be found on the FDA’s EUA page.
As cord blood inventory increases, use declines
Recently, the US has seen a decline in the use of cord blood in transplants, according to a study by the RAND Corporation.
The research revealed a significant increase in the national cord blood inventory but also suggested many cord blood units may go unused because they have a total nucleated cell (TNC) count of less than 1.25 billion cells per unit.
RAND researchers conducted this study by examining past research about cord blood banks, analyzing data on public cord blood bank collection and use, and interviewing stakeholders such as blood bank leaders and transplant center physicians.
The data showed the number of hematopoietic stem cell transplants (HSCTs) performed in the US has increased in recent years.
However, the percentage of HSCTs in which cord blood is used has declined, from about 12% (n=822) of all HSCTs in 2010 to about 8% (n=718) of all HSCTs in 2015.
At the same time, public cord blood banks in the US have greatly increased their inventory. This is, at least in part, because the federal government began offering subsidies to public contractor banks with the goal of helping them obtain 150,000 new units of high-quality cord blood.
The numeric goal has been met, as the inventory currently exceeds 200,000 units. However, many of the units cannot be considered high-quality because they have a TNC count of less than 1.25 billion cells.
The researchers noted that the government subsidies are not structured to discourage the processing and banking of cord blood units with lower TNC counts.
In fact, the team found that about half of the national inventory is made up of cord blood units with TNC counts of less than 1.25 billion cells. They said the probability that such a unit will be used in a given year is about 0.1%, and there’s an 11% chance it will ever be used.
On the other hand, there is a 1% to 3% chance a cord blood unit with a TNC count of more than 1.5 billion will be used in a given year, and there’s a 61% chance it will ever be used.
Therefore, the researchers recommend the federal government find ways to encourage public cord blood banks to collect samples with higher TNC counts, as they will help expand the utility of the national inventory.
Support for this research was provided by the US Department of Health and Human Services, Office of the Assistant Secretary of Health.
Recently, the US has seen a decline in the use of cord blood in transplants, according to a study by the RAND Corporation.
The research revealed a significant increase in the national cord blood inventory but also suggested many cord blood units may go unused because they have a total nucleated cell (TNC) count of less than 1.25 billion cells per unit.
RAND researchers conducted this study by examining past research about cord blood banks, analyzing data on public cord blood bank collection and use, and interviewing stakeholders such as blood bank leaders and transplant center physicians.
The data showed the number of hematopoietic stem cell transplants (HSCTs) performed in the US has increased in recent years.
However, the percentage of HSCTs in which cord blood is used has declined, from about 12% (n=822) of all HSCTs in 2010 to about 8% (n=718) of all HSCTs in 2015.
At the same time, public cord blood banks in the US have greatly increased their inventory. This is, at least in part, because the federal government began offering subsidies to public contractor banks with the goal of helping them obtain 150,000 new units of high-quality cord blood.
The numeric goal has been met, as the inventory currently exceeds 200,000 units. However, many of the units cannot be considered high-quality because they have a TNC count of less than 1.25 billion cells.
The researchers noted that the government subsidies are not structured to discourage the processing and banking of cord blood units with lower TNC counts.
In fact, the team found that about half of the national inventory is made up of cord blood units with TNC counts of less than 1.25 billion cells. They said the probability that such a unit will be used in a given year is about 0.1%, and there’s an 11% chance it will ever be used.
On the other hand, there is a 1% to 3% chance a cord blood unit with a TNC count of more than 1.5 billion will be used in a given year, and there’s a 61% chance it will ever be used.
Therefore, the researchers recommend the federal government find ways to encourage public cord blood banks to collect samples with higher TNC counts, as they will help expand the utility of the national inventory.
Support for this research was provided by the US Department of Health and Human Services, Office of the Assistant Secretary of Health.
Recently, the US has seen a decline in the use of cord blood in transplants, according to a study by the RAND Corporation.
The research revealed a significant increase in the national cord blood inventory but also suggested many cord blood units may go unused because they have a total nucleated cell (TNC) count of less than 1.25 billion cells per unit.
RAND researchers conducted this study by examining past research about cord blood banks, analyzing data on public cord blood bank collection and use, and interviewing stakeholders such as blood bank leaders and transplant center physicians.
The data showed the number of hematopoietic stem cell transplants (HSCTs) performed in the US has increased in recent years.
However, the percentage of HSCTs in which cord blood is used has declined, from about 12% (n=822) of all HSCTs in 2010 to about 8% (n=718) of all HSCTs in 2015.
At the same time, public cord blood banks in the US have greatly increased their inventory. This is, at least in part, because the federal government began offering subsidies to public contractor banks with the goal of helping them obtain 150,000 new units of high-quality cord blood.
The numeric goal has been met, as the inventory currently exceeds 200,000 units. However, many of the units cannot be considered high-quality because they have a TNC count of less than 1.25 billion cells.
The researchers noted that the government subsidies are not structured to discourage the processing and banking of cord blood units with lower TNC counts.
In fact, the team found that about half of the national inventory is made up of cord blood units with TNC counts of less than 1.25 billion cells. They said the probability that such a unit will be used in a given year is about 0.1%, and there’s an 11% chance it will ever be used.
On the other hand, there is a 1% to 3% chance a cord blood unit with a TNC count of more than 1.5 billion will be used in a given year, and there’s a 61% chance it will ever be used.
Therefore, the researchers recommend the federal government find ways to encourage public cord blood banks to collect samples with higher TNC counts, as they will help expand the utility of the national inventory.
Support for this research was provided by the US Department of Health and Human Services, Office of the Assistant Secretary of Health.
Doc advocates depression screening for cancer patients
SAN DIEGO—New research suggests a need for mental health screening among cancer patients.
The study revealed a 40% rate of depression among patients treated at an urban cancer center over a 3-year period.
Three-quarters of the depressed patients were previously undiagnosed.
Female patients and those who were unable to work due to disability were more likely to be depressed.
Jason Domogauer, PhD, of Rutgers New Jersey Medical School in Newark, New Jersey, presented these findings at ASTRO’s 59th Annual Meeting.
“Depression is widely recognized as an underdiagnosed disorder, particularly among older adults and cancer patients,” Dr Domogauer said. “Our findings point to a clear need for action, including depression screening during initial and continuing patient visits, initiation of mental health treatments for identified patients, and increased collaboration with mental health providers in cancer treatment centers. These efforts are particularly important for patients in urban centers, those who are female, and those who are unable to work because of their disease.”
Dr Domogauer and his colleagues studied 400 cancer patients who received treatment at Rutgers New Jersey Medical School/University Hospital Cancer Center between 2013 and 2016.
The average patient age was 55 (range, 20-86), and 53% of patients were female. Forty-eight percent of patients were African-American, 29% were non-Hispanic white, and 16% were Hispanic.
Nearly equal numbers of patients reported being able to work (49%) or unable to work due to disability (51%). Most patients (85%) received radiation as part of their cancer treatment.
The researchers assessed depression in the patients using a minimum score of 16 on the Center for Epidemiologic Studies Depression Scale.
In this way, 40% of the patients were diagnosed with depression. In 75% of these patients, depression was previously undiagnosed. This means roughly 30% of the overall patient population suffered from undiagnosed and untreated depression.
Depression was more common among females than males—47% and 32%, respectively (odds ratio [OR]=1.9, P=0.007).
Depression was also more likely among patients who were unable to work due to disability—48%, compared to 33% of those able to work (OR=1.9, P=0.005).
Depression prevalence did not differ significantly among racial/ethnic groups.
When the researchers looked specifically at patients who were previously not diagnosed with depression, the effects of being female or unable to work persisted.
In this subgroup, depression was more common among women than men—43% and 29%, respectively (OR=1.9, P=0.02)—and patients with disability compared to able patients—43% and 31%, respectively (OR=1.7, P=0.03).
SAN DIEGO—New research suggests a need for mental health screening among cancer patients.
The study revealed a 40% rate of depression among patients treated at an urban cancer center over a 3-year period.
Three-quarters of the depressed patients were previously undiagnosed.
Female patients and those who were unable to work due to disability were more likely to be depressed.
Jason Domogauer, PhD, of Rutgers New Jersey Medical School in Newark, New Jersey, presented these findings at ASTRO’s 59th Annual Meeting.
“Depression is widely recognized as an underdiagnosed disorder, particularly among older adults and cancer patients,” Dr Domogauer said. “Our findings point to a clear need for action, including depression screening during initial and continuing patient visits, initiation of mental health treatments for identified patients, and increased collaboration with mental health providers in cancer treatment centers. These efforts are particularly important for patients in urban centers, those who are female, and those who are unable to work because of their disease.”
Dr Domogauer and his colleagues studied 400 cancer patients who received treatment at Rutgers New Jersey Medical School/University Hospital Cancer Center between 2013 and 2016.
The average patient age was 55 (range, 20-86), and 53% of patients were female. Forty-eight percent of patients were African-American, 29% were non-Hispanic white, and 16% were Hispanic.
Nearly equal numbers of patients reported being able to work (49%) or unable to work due to disability (51%). Most patients (85%) received radiation as part of their cancer treatment.
The researchers assessed depression in the patients using a minimum score of 16 on the Center for Epidemiologic Studies Depression Scale.
In this way, 40% of the patients were diagnosed with depression. In 75% of these patients, depression was previously undiagnosed. This means roughly 30% of the overall patient population suffered from undiagnosed and untreated depression.
Depression was more common among females than males—47% and 32%, respectively (odds ratio [OR]=1.9, P=0.007).
Depression was also more likely among patients who were unable to work due to disability—48%, compared to 33% of those able to work (OR=1.9, P=0.005).
Depression prevalence did not differ significantly among racial/ethnic groups.
When the researchers looked specifically at patients who were previously not diagnosed with depression, the effects of being female or unable to work persisted.
In this subgroup, depression was more common among women than men—43% and 29%, respectively (OR=1.9, P=0.02)—and patients with disability compared to able patients—43% and 31%, respectively (OR=1.7, P=0.03).
SAN DIEGO—New research suggests a need for mental health screening among cancer patients.
The study revealed a 40% rate of depression among patients treated at an urban cancer center over a 3-year period.
Three-quarters of the depressed patients were previously undiagnosed.
Female patients and those who were unable to work due to disability were more likely to be depressed.
Jason Domogauer, PhD, of Rutgers New Jersey Medical School in Newark, New Jersey, presented these findings at ASTRO’s 59th Annual Meeting.
“Depression is widely recognized as an underdiagnosed disorder, particularly among older adults and cancer patients,” Dr Domogauer said. “Our findings point to a clear need for action, including depression screening during initial and continuing patient visits, initiation of mental health treatments for identified patients, and increased collaboration with mental health providers in cancer treatment centers. These efforts are particularly important for patients in urban centers, those who are female, and those who are unable to work because of their disease.”
Dr Domogauer and his colleagues studied 400 cancer patients who received treatment at Rutgers New Jersey Medical School/University Hospital Cancer Center between 2013 and 2016.
The average patient age was 55 (range, 20-86), and 53% of patients were female. Forty-eight percent of patients were African-American, 29% were non-Hispanic white, and 16% were Hispanic.
Nearly equal numbers of patients reported being able to work (49%) or unable to work due to disability (51%). Most patients (85%) received radiation as part of their cancer treatment.
The researchers assessed depression in the patients using a minimum score of 16 on the Center for Epidemiologic Studies Depression Scale.
In this way, 40% of the patients were diagnosed with depression. In 75% of these patients, depression was previously undiagnosed. This means roughly 30% of the overall patient population suffered from undiagnosed and untreated depression.
Depression was more common among females than males—47% and 32%, respectively (odds ratio [OR]=1.9, P=0.007).
Depression was also more likely among patients who were unable to work due to disability—48%, compared to 33% of those able to work (OR=1.9, P=0.005).
Depression prevalence did not differ significantly among racial/ethnic groups.
When the researchers looked specifically at patients who were previously not diagnosed with depression, the effects of being female or unable to work persisted.
In this subgroup, depression was more common among women than men—43% and 29%, respectively (OR=1.9, P=0.02)—and patients with disability compared to able patients—43% and 31%, respectively (OR=1.7, P=0.03).
Japan approves product for hemophilia A
Japan’s Ministry of Health, Labor and Welfare has approved lonoctocog alfa (AFSTYLA®), a recombinant single-chain coagulation factor VIII product, for use in patients with hemophilia A.
The product is approved for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding, and for perioperative management.
Lonoctocog alfa is the first and only single-chain recombinant factor VIII product specifically designed to treat hemophilia A.
According to CSL Behring, the company developing lonoctocog alfa, the product was designed to provide greater molecular stability and longer duration of action. Lonoctocog alfa uses a covalent bond to form one structural entity, a single polypeptide chain, to improve the stability of factor VIII and provide factor VIII activity with the option of twice-weekly dosing.
Lonoctocog alfa is also approved in the European Union, US, Canada, Switzerland, and Australia.
AFFINITY trials
Japan’s approval of lonoctocog alfa is based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).
Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12.
In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.
Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.
Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.
Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).
One patient withdrew from treatment due to hypersensitivity.
None of the patients developed neutralizing antibodies to factor VIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.
Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were published in the Journal of Thrombosis and Haemostasis in March 2017.
Japan’s Ministry of Health, Labor and Welfare has approved lonoctocog alfa (AFSTYLA®), a recombinant single-chain coagulation factor VIII product, for use in patients with hemophilia A.
The product is approved for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding, and for perioperative management.
Lonoctocog alfa is the first and only single-chain recombinant factor VIII product specifically designed to treat hemophilia A.
According to CSL Behring, the company developing lonoctocog alfa, the product was designed to provide greater molecular stability and longer duration of action. Lonoctocog alfa uses a covalent bond to form one structural entity, a single polypeptide chain, to improve the stability of factor VIII and provide factor VIII activity with the option of twice-weekly dosing.
Lonoctocog alfa is also approved in the European Union, US, Canada, Switzerland, and Australia.
AFFINITY trials
Japan’s approval of lonoctocog alfa is based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).
Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12.
In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.
Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.
Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.
Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).
One patient withdrew from treatment due to hypersensitivity.
None of the patients developed neutralizing antibodies to factor VIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.
Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were published in the Journal of Thrombosis and Haemostasis in March 2017.
Japan’s Ministry of Health, Labor and Welfare has approved lonoctocog alfa (AFSTYLA®), a recombinant single-chain coagulation factor VIII product, for use in patients with hemophilia A.
The product is approved for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding, and for perioperative management.
Lonoctocog alfa is the first and only single-chain recombinant factor VIII product specifically designed to treat hemophilia A.
According to CSL Behring, the company developing lonoctocog alfa, the product was designed to provide greater molecular stability and longer duration of action. Lonoctocog alfa uses a covalent bond to form one structural entity, a single polypeptide chain, to improve the stability of factor VIII and provide factor VIII activity with the option of twice-weekly dosing.
Lonoctocog alfa is also approved in the European Union, US, Canada, Switzerland, and Australia.
AFFINITY trials
Japan’s approval of lonoctocog alfa is based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).
Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12.
In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.
Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.
Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.
Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).
One patient withdrew from treatment due to hypersensitivity.
None of the patients developed neutralizing antibodies to factor VIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.
Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were published in the Journal of Thrombosis and Haemostasis in March 2017.
Maintenance will be a new standard in MCL, doc says
Results of a phase 3 trial suggest rituximab maintenance after transplant can prolong survival in non-elderly patients with mantle cell lymphoma (MCL).
Compared to patients who did not receive maintenance, those who received rituximab every other month for 3 years after autologous transplant had superior event-free survival (EFS), progression-free survival (PFS), and overall survival (OS).
Researchers reported these results in NEJM. The study was funded by Roche and Amgen.
“We demonstrate, with this study, that treatment with immunotherapy can delay the onset of relapse and prolong the survival of patients,” said study author Steven Le Gouill, MD, PhD, of CHU de Nantes in France.*
“It is clear that the use of rituximab maintenance after chemotherapy in this type of lymphoma will become a new standard of treatment.”
Dr Le Gouill and his colleagues began this study with 299 MCL patients. Their median age was 57 (range, 27-65), and 79% were male. Most had Ann Arbor stage IV disease (84%), followed by III (10%), and II (6%).
According to MIPI, 53% of patients had low-risk disease, 27% had intermediate-risk MCL, and 19% had high-risk disease. Ninety-four percent of patients had an ECOG performance status score below 3.
Treatment
Patients first received 4 courses of induction with R-DHAP (rituximab, dexamethasone, cytarabine, and a platinum derivative [carboplatin, oxaliplatin, or cisplatin]).
The overall response rate was 94%, with 41% (n=124) achieving a complete response (CR) and 36% (n=107) achieving an unconfirmed CR.
Twenty patients who had an insufficient response then received 4 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Eleven of these patients went on to receive an autologous hematopoietic stem cell transplant (HSCT).
In all, 257 patients (86%) underwent autologous HSCT. The conditioning regimen was R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).
Sixty-five percent of patients (n=168) achieved a CR after HSCT, and 24% (n=61) had an unconfirmed CR.
Up to 3 months after HSCT, patients were randomized to observation (n=120) or to receive rituximab (375 mg/m2) every 2 months for 3 years (n=120).
The researchers said there were no significant differences between these 2 groups regarding characteristics at study enrollment or the patients’ disease status at randomization.
Results
The median follow-up from randomization was 50.2 months (range, 46.4 to 54.2). The median EFS, PFS, and OS were not reached in either group.
The 4-year EFS was 79% in the rituximab group and 61% in the observation group (P=0.001). The 4-year PFS was 83% and 64%, respectively (P<0.001). And the 4-year OS was 89% and 80%, respectively (P=0.04).
Of the 11 patients who received R-CHOP before randomization, 4 were randomized to the rituximab group and 7 to the observation group.
One patient in the rituximab group relapsed and died. The other 3 were still alive and disease-free at the final analysis.
In the observation group, 4 patients had relapsed but were alive as of the final analysis, while 3 patients had died.
There were 59 patients who did not undergo randomization (due to disease progression, death, HSCT ineligibility, toxic effects, and other reasons).
For these patients, the median PFS was 11.0 months, and the median OS was 30.6 months.
*Quote has been translated from French.
Results of a phase 3 trial suggest rituximab maintenance after transplant can prolong survival in non-elderly patients with mantle cell lymphoma (MCL).
Compared to patients who did not receive maintenance, those who received rituximab every other month for 3 years after autologous transplant had superior event-free survival (EFS), progression-free survival (PFS), and overall survival (OS).
Researchers reported these results in NEJM. The study was funded by Roche and Amgen.
“We demonstrate, with this study, that treatment with immunotherapy can delay the onset of relapse and prolong the survival of patients,” said study author Steven Le Gouill, MD, PhD, of CHU de Nantes in France.*
“It is clear that the use of rituximab maintenance after chemotherapy in this type of lymphoma will become a new standard of treatment.”
Dr Le Gouill and his colleagues began this study with 299 MCL patients. Their median age was 57 (range, 27-65), and 79% were male. Most had Ann Arbor stage IV disease (84%), followed by III (10%), and II (6%).
According to MIPI, 53% of patients had low-risk disease, 27% had intermediate-risk MCL, and 19% had high-risk disease. Ninety-four percent of patients had an ECOG performance status score below 3.
Treatment
Patients first received 4 courses of induction with R-DHAP (rituximab, dexamethasone, cytarabine, and a platinum derivative [carboplatin, oxaliplatin, or cisplatin]).
The overall response rate was 94%, with 41% (n=124) achieving a complete response (CR) and 36% (n=107) achieving an unconfirmed CR.
Twenty patients who had an insufficient response then received 4 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Eleven of these patients went on to receive an autologous hematopoietic stem cell transplant (HSCT).
In all, 257 patients (86%) underwent autologous HSCT. The conditioning regimen was R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).
Sixty-five percent of patients (n=168) achieved a CR after HSCT, and 24% (n=61) had an unconfirmed CR.
Up to 3 months after HSCT, patients were randomized to observation (n=120) or to receive rituximab (375 mg/m2) every 2 months for 3 years (n=120).
The researchers said there were no significant differences between these 2 groups regarding characteristics at study enrollment or the patients’ disease status at randomization.
Results
The median follow-up from randomization was 50.2 months (range, 46.4 to 54.2). The median EFS, PFS, and OS were not reached in either group.
The 4-year EFS was 79% in the rituximab group and 61% in the observation group (P=0.001). The 4-year PFS was 83% and 64%, respectively (P<0.001). And the 4-year OS was 89% and 80%, respectively (P=0.04).
Of the 11 patients who received R-CHOP before randomization, 4 were randomized to the rituximab group and 7 to the observation group.
One patient in the rituximab group relapsed and died. The other 3 were still alive and disease-free at the final analysis.
In the observation group, 4 patients had relapsed but were alive as of the final analysis, while 3 patients had died.
There were 59 patients who did not undergo randomization (due to disease progression, death, HSCT ineligibility, toxic effects, and other reasons).
For these patients, the median PFS was 11.0 months, and the median OS was 30.6 months.
*Quote has been translated from French.
Results of a phase 3 trial suggest rituximab maintenance after transplant can prolong survival in non-elderly patients with mantle cell lymphoma (MCL).
Compared to patients who did not receive maintenance, those who received rituximab every other month for 3 years after autologous transplant had superior event-free survival (EFS), progression-free survival (PFS), and overall survival (OS).
Researchers reported these results in NEJM. The study was funded by Roche and Amgen.
“We demonstrate, with this study, that treatment with immunotherapy can delay the onset of relapse and prolong the survival of patients,” said study author Steven Le Gouill, MD, PhD, of CHU de Nantes in France.*
“It is clear that the use of rituximab maintenance after chemotherapy in this type of lymphoma will become a new standard of treatment.”
Dr Le Gouill and his colleagues began this study with 299 MCL patients. Their median age was 57 (range, 27-65), and 79% were male. Most had Ann Arbor stage IV disease (84%), followed by III (10%), and II (6%).
According to MIPI, 53% of patients had low-risk disease, 27% had intermediate-risk MCL, and 19% had high-risk disease. Ninety-four percent of patients had an ECOG performance status score below 3.
Treatment
Patients first received 4 courses of induction with R-DHAP (rituximab, dexamethasone, cytarabine, and a platinum derivative [carboplatin, oxaliplatin, or cisplatin]).
The overall response rate was 94%, with 41% (n=124) achieving a complete response (CR) and 36% (n=107) achieving an unconfirmed CR.
Twenty patients who had an insufficient response then received 4 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Eleven of these patients went on to receive an autologous hematopoietic stem cell transplant (HSCT).
In all, 257 patients (86%) underwent autologous HSCT. The conditioning regimen was R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).
Sixty-five percent of patients (n=168) achieved a CR after HSCT, and 24% (n=61) had an unconfirmed CR.
Up to 3 months after HSCT, patients were randomized to observation (n=120) or to receive rituximab (375 mg/m2) every 2 months for 3 years (n=120).
The researchers said there were no significant differences between these 2 groups regarding characteristics at study enrollment or the patients’ disease status at randomization.
Results
The median follow-up from randomization was 50.2 months (range, 46.4 to 54.2). The median EFS, PFS, and OS were not reached in either group.
The 4-year EFS was 79% in the rituximab group and 61% in the observation group (P=0.001). The 4-year PFS was 83% and 64%, respectively (P<0.001). And the 4-year OS was 89% and 80%, respectively (P=0.04).
Of the 11 patients who received R-CHOP before randomization, 4 were randomized to the rituximab group and 7 to the observation group.
One patient in the rituximab group relapsed and died. The other 3 were still alive and disease-free at the final analysis.
In the observation group, 4 patients had relapsed but were alive as of the final analysis, while 3 patients had died.
There were 59 patients who did not undergo randomization (due to disease progression, death, HSCT ineligibility, toxic effects, and other reasons).
For these patients, the median PFS was 11.0 months, and the median OS was 30.6 months.
*Quote has been translated from French.
Drugs could improve treatment of CML
Preclinical research suggests 2 drugs already approved for use in the US may improve upon tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML).
The drugs are prostaglandin E1 (PGE1), which is used to treat erectile dysfunction, and misoprostol, which is used to prevent stomach ulcers.
Researchers found that each of these drugs could suppress leukemic stem cells (LSCs) and enhance the activity of imatinib in mice with CML.
Hai-Hui (Howard) Xue, MD, PhD, of University of Iowa in Iowa City, and his colleagues reported these findings in Cell Stem Cell.
“A successful treatment [for CML] is expected to kill the bulk leukemia cells and, at the same time, get rid of the leukemic stem cells,” Dr Xue said. “Potentially, that could lead to a cure.”
Therefore, Dr Xue and his colleagues set out to find drugs that could eradicate LSCs.
The researchers had previously shown that CML LSCs are “strongly dependent” on 2 transcription factors—Tcf1 and Lef1—for self-renewal, whereas normal hematopoietic stem and progenitor cells are not.
With their current research, the team found that Tcf1/Lef1 deficiency “at least partly impairs the transcriptional program” that maintains LSCs in mice and humans with CML.
So the researchers used connectivity maps to identify molecules that could replicate Tcf1/Lef1 deficiency. This screen revealed PGE1.
The team found that PGE1 inhibited the activity and self-renewal of CML LSCs. And the combination of PGE1 and imatinib could reduce leukemia growth in mouse models of CML.
When the mice received no treatment or imatinib alone, LSCs persisted. However, PGE1 enhanced the efficacy of imatinib, and mice that received this combination saw their LSCs “greatly diminished.”
The researchers then transplanted LSCs from these mice into secondary hosts and monitored their survival without administering additional treatment.
Mice that received PGE1-pretreated LSCs lived significantly longer (P<0.001) than mice that received imatinib-pretreated LSCs. And mice that received LSCs pretreated with PGE1 and imatinib lived significantly longer than mice that received PGE1-pretreated LSCs (P=0.039).
Investigating how PGE1 works to suppress LSCs, the researchers found the effect relies on a critical interaction between PGE1 and its receptor, EP4.
So the team tested misoprostol, which also interacts with EP4, in mice with CML.
The researchers found that misoprostol alone diminished LSCs, and the combination of misoprostol and imatinib “exhibited stronger effects.”
In addition, mice that received LSCs from animals previously treated with misoprostol survived longer and had a reduction in leukemia burden compared to mice that received untreated LSCs.
“We would like to be able to test these compounds in a clinical trial,” Dr Xue said. “If we could show that the combination of TKI with PGE1 or misoprostol can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”
Preclinical research suggests 2 drugs already approved for use in the US may improve upon tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML).
The drugs are prostaglandin E1 (PGE1), which is used to treat erectile dysfunction, and misoprostol, which is used to prevent stomach ulcers.
Researchers found that each of these drugs could suppress leukemic stem cells (LSCs) and enhance the activity of imatinib in mice with CML.
Hai-Hui (Howard) Xue, MD, PhD, of University of Iowa in Iowa City, and his colleagues reported these findings in Cell Stem Cell.
“A successful treatment [for CML] is expected to kill the bulk leukemia cells and, at the same time, get rid of the leukemic stem cells,” Dr Xue said. “Potentially, that could lead to a cure.”
Therefore, Dr Xue and his colleagues set out to find drugs that could eradicate LSCs.
The researchers had previously shown that CML LSCs are “strongly dependent” on 2 transcription factors—Tcf1 and Lef1—for self-renewal, whereas normal hematopoietic stem and progenitor cells are not.
With their current research, the team found that Tcf1/Lef1 deficiency “at least partly impairs the transcriptional program” that maintains LSCs in mice and humans with CML.
So the researchers used connectivity maps to identify molecules that could replicate Tcf1/Lef1 deficiency. This screen revealed PGE1.
The team found that PGE1 inhibited the activity and self-renewal of CML LSCs. And the combination of PGE1 and imatinib could reduce leukemia growth in mouse models of CML.
When the mice received no treatment or imatinib alone, LSCs persisted. However, PGE1 enhanced the efficacy of imatinib, and mice that received this combination saw their LSCs “greatly diminished.”
The researchers then transplanted LSCs from these mice into secondary hosts and monitored their survival without administering additional treatment.
Mice that received PGE1-pretreated LSCs lived significantly longer (P<0.001) than mice that received imatinib-pretreated LSCs. And mice that received LSCs pretreated with PGE1 and imatinib lived significantly longer than mice that received PGE1-pretreated LSCs (P=0.039).
Investigating how PGE1 works to suppress LSCs, the researchers found the effect relies on a critical interaction between PGE1 and its receptor, EP4.
So the team tested misoprostol, which also interacts with EP4, in mice with CML.
The researchers found that misoprostol alone diminished LSCs, and the combination of misoprostol and imatinib “exhibited stronger effects.”
In addition, mice that received LSCs from animals previously treated with misoprostol survived longer and had a reduction in leukemia burden compared to mice that received untreated LSCs.
“We would like to be able to test these compounds in a clinical trial,” Dr Xue said. “If we could show that the combination of TKI with PGE1 or misoprostol can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”
Preclinical research suggests 2 drugs already approved for use in the US may improve upon tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML).
The drugs are prostaglandin E1 (PGE1), which is used to treat erectile dysfunction, and misoprostol, which is used to prevent stomach ulcers.
Researchers found that each of these drugs could suppress leukemic stem cells (LSCs) and enhance the activity of imatinib in mice with CML.
Hai-Hui (Howard) Xue, MD, PhD, of University of Iowa in Iowa City, and his colleagues reported these findings in Cell Stem Cell.
“A successful treatment [for CML] is expected to kill the bulk leukemia cells and, at the same time, get rid of the leukemic stem cells,” Dr Xue said. “Potentially, that could lead to a cure.”
Therefore, Dr Xue and his colleagues set out to find drugs that could eradicate LSCs.
The researchers had previously shown that CML LSCs are “strongly dependent” on 2 transcription factors—Tcf1 and Lef1—for self-renewal, whereas normal hematopoietic stem and progenitor cells are not.
With their current research, the team found that Tcf1/Lef1 deficiency “at least partly impairs the transcriptional program” that maintains LSCs in mice and humans with CML.
So the researchers used connectivity maps to identify molecules that could replicate Tcf1/Lef1 deficiency. This screen revealed PGE1.
The team found that PGE1 inhibited the activity and self-renewal of CML LSCs. And the combination of PGE1 and imatinib could reduce leukemia growth in mouse models of CML.
When the mice received no treatment or imatinib alone, LSCs persisted. However, PGE1 enhanced the efficacy of imatinib, and mice that received this combination saw their LSCs “greatly diminished.”
The researchers then transplanted LSCs from these mice into secondary hosts and monitored their survival without administering additional treatment.
Mice that received PGE1-pretreated LSCs lived significantly longer (P<0.001) than mice that received imatinib-pretreated LSCs. And mice that received LSCs pretreated with PGE1 and imatinib lived significantly longer than mice that received PGE1-pretreated LSCs (P=0.039).
Investigating how PGE1 works to suppress LSCs, the researchers found the effect relies on a critical interaction between PGE1 and its receptor, EP4.
So the team tested misoprostol, which also interacts with EP4, in mice with CML.
The researchers found that misoprostol alone diminished LSCs, and the combination of misoprostol and imatinib “exhibited stronger effects.”
In addition, mice that received LSCs from animals previously treated with misoprostol survived longer and had a reduction in leukemia burden compared to mice that received untreated LSCs.
“We would like to be able to test these compounds in a clinical trial,” Dr Xue said. “If we could show that the combination of TKI with PGE1 or misoprostol can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”