User login
Drug exhibits preclinical activity against MDS
Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).
Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).
APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.
The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.
“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.
Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.
By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.
Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.
Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.
On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.
When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.
They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.
Baseline BFU-E number affects response
The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.
Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).
However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).
The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).
The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).
Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.
“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.
Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months. 
Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).
Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).
APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.
The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.
“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.
Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.
By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.
Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.
Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.
On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.
When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.
They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.
Baseline BFU-E number affects response
The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.
Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).
However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).
The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).
The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).
Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.
“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.
Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.
Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).
Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).
APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.
The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.
“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.
Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.
By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.
Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.
Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.
On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.
When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.
They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.
Baseline BFU-E number affects response
The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.
Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).
However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).
The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).
The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).
Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.
“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.
Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.
mAb gets breakthrough designation for HLH
Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.
NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.
The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.
“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.
The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.
The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Efficacy
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.
Safety
No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.
There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.
The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.
NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.
The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.
“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.
The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.
The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Efficacy
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.
Safety
No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.
There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.
The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.
NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.
The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.
“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.
The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.
The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Efficacy
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.
Safety
No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.
There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.
The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Drug may best BSC in some high-risk MDS patients
Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).
Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).
However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.
The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.
The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).
At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).
However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:
- Patients younger than 75 years of age (HR=0.55, P=0.0010)
- Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
- Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
- Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
- Patients with monosomy 7 (HR=0.26, P=0.0041)
- Patients with trisomy 8 (HR=0.28, P=0.0083).
The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).
Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.
“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”
INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.
The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).
Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).
Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).
However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.
The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.
The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).
At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).
However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:
- Patients younger than 75 years of age (HR=0.55, P=0.0010)
- Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
- Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
- Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
- Patients with monosomy 7 (HR=0.26, P=0.0041)
- Patients with trisomy 8 (HR=0.28, P=0.0083).
The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).
Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.
“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”
INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.
The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).
Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).
Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).
However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.
The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.
The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).
At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).
However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:
- Patients younger than 75 years of age (HR=0.55, P=0.0010)
- Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
- Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
- Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
- Patients with monosomy 7 (HR=0.26, P=0.0041)
- Patients with trisomy 8 (HR=0.28, P=0.0083).
The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).
Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.
“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”
INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.
The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).
Germline mutations linked to hematologic malignancies
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
System could aid assessment of sickle cell disease
and a normal one
Image by Betty Pace
A microfluidic system can measure the deformability and adhesion of red blood cells (RBCs) in samples from patients with sickle cell disease (SCD), according to research published in Technology.
The researchers noted that RBC deformability has been associated with vaso-occlusion in SCD, but we have limited knowledge on deformation characteristics of RBCs adhered to endothelium-associated proteins in microphysiological fluid flow conditions.
In the past, various approaches have been used to measure RBC deformability, including optical tweezers, micropipette aspiration, and atomic force microscopy. These methods have enabled sensitive and controlled measurement of RBC mechanical properties, but they are typically performed in open environments without fluid flow.
“Microfluidic techniques allow incorporation of physiological flow conditions, as well as biologically relevant adhesion surfaces in a closed setting, which better mimic the natural physiological environment of the RBCs in blood flow,” said study author Umut Gurkan, PhD, of the Case Western Reserve University in Cleveland, Ohio.
For their system, Dr Gurkan and his colleagues integrated a microfluidic approach with a cell-dimensioning algorithm.
They introduced a new parameter to assess the deformability of RBCs. It is known as the dynamic deformability index (DDI), which they defined as the time-dependent change of the cell’s aspect ratio in response to fluid flow shear stress.
The researchers assessed the deformability and adhesion of RBCs containing healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS). And they found the DDI of HbS-containing RBCs was significantly lower than the DDI of HbA-containing RBCs.
The team also found they could divide HbS-containing RBCs into 2 groups—deformable and non-deformable RBCs.
“We report, for the first time, on the subpopulations of RBCs in terms of dynamic deformation characteristics in SCD: deformable and non-deformable RBCs,” said Yunus Alapan, a PhD candidate at Case Western Reserve University.
“Furthermore, we analyzed adhesion of non-deformable RBCs, in comparison to deformable RBCs, quantitatively at physiological and above physiological flow shear stresses in blood samples obtained from SCD patients.”
“We observed significantly greater numbers of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.”
Now, the researchers are working to further characterize deformability and adhesion of RBCs in a greater number of SCD patients to analyze their associations with clinical phenotypes and complications.
The team said their system may provide important biophysical insights into disease pathophysiology when widely applied in SCD.
They also believe the microfluidic platform has the potential to be used as an in vitro assay for monitoring disease activity at baseline, during clinical flux after treatment, during painful episodes, and in association with long-term complications.
and a normal one
Image by Betty Pace
A microfluidic system can measure the deformability and adhesion of red blood cells (RBCs) in samples from patients with sickle cell disease (SCD), according to research published in Technology.
The researchers noted that RBC deformability has been associated with vaso-occlusion in SCD, but we have limited knowledge on deformation characteristics of RBCs adhered to endothelium-associated proteins in microphysiological fluid flow conditions.
In the past, various approaches have been used to measure RBC deformability, including optical tweezers, micropipette aspiration, and atomic force microscopy. These methods have enabled sensitive and controlled measurement of RBC mechanical properties, but they are typically performed in open environments without fluid flow.
“Microfluidic techniques allow incorporation of physiological flow conditions, as well as biologically relevant adhesion surfaces in a closed setting, which better mimic the natural physiological environment of the RBCs in blood flow,” said study author Umut Gurkan, PhD, of the Case Western Reserve University in Cleveland, Ohio.
For their system, Dr Gurkan and his colleagues integrated a microfluidic approach with a cell-dimensioning algorithm.
They introduced a new parameter to assess the deformability of RBCs. It is known as the dynamic deformability index (DDI), which they defined as the time-dependent change of the cell’s aspect ratio in response to fluid flow shear stress.
The researchers assessed the deformability and adhesion of RBCs containing healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS). And they found the DDI of HbS-containing RBCs was significantly lower than the DDI of HbA-containing RBCs.
The team also found they could divide HbS-containing RBCs into 2 groups—deformable and non-deformable RBCs.
“We report, for the first time, on the subpopulations of RBCs in terms of dynamic deformation characteristics in SCD: deformable and non-deformable RBCs,” said Yunus Alapan, a PhD candidate at Case Western Reserve University.
“Furthermore, we analyzed adhesion of non-deformable RBCs, in comparison to deformable RBCs, quantitatively at physiological and above physiological flow shear stresses in blood samples obtained from SCD patients.”
“We observed significantly greater numbers of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.”
Now, the researchers are working to further characterize deformability and adhesion of RBCs in a greater number of SCD patients to analyze their associations with clinical phenotypes and complications.
The team said their system may provide important biophysical insights into disease pathophysiology when widely applied in SCD.
They also believe the microfluidic platform has the potential to be used as an in vitro assay for monitoring disease activity at baseline, during clinical flux after treatment, during painful episodes, and in association with long-term complications.
and a normal one
Image by Betty Pace
A microfluidic system can measure the deformability and adhesion of red blood cells (RBCs) in samples from patients with sickle cell disease (SCD), according to research published in Technology.
The researchers noted that RBC deformability has been associated with vaso-occlusion in SCD, but we have limited knowledge on deformation characteristics of RBCs adhered to endothelium-associated proteins in microphysiological fluid flow conditions.
In the past, various approaches have been used to measure RBC deformability, including optical tweezers, micropipette aspiration, and atomic force microscopy. These methods have enabled sensitive and controlled measurement of RBC mechanical properties, but they are typically performed in open environments without fluid flow.
“Microfluidic techniques allow incorporation of physiological flow conditions, as well as biologically relevant adhesion surfaces in a closed setting, which better mimic the natural physiological environment of the RBCs in blood flow,” said study author Umut Gurkan, PhD, of the Case Western Reserve University in Cleveland, Ohio.
For their system, Dr Gurkan and his colleagues integrated a microfluidic approach with a cell-dimensioning algorithm.
They introduced a new parameter to assess the deformability of RBCs. It is known as the dynamic deformability index (DDI), which they defined as the time-dependent change of the cell’s aspect ratio in response to fluid flow shear stress.
The researchers assessed the deformability and adhesion of RBCs containing healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS). And they found the DDI of HbS-containing RBCs was significantly lower than the DDI of HbA-containing RBCs.
The team also found they could divide HbS-containing RBCs into 2 groups—deformable and non-deformable RBCs.
“We report, for the first time, on the subpopulations of RBCs in terms of dynamic deformation characteristics in SCD: deformable and non-deformable RBCs,” said Yunus Alapan, a PhD candidate at Case Western Reserve University.
“Furthermore, we analyzed adhesion of non-deformable RBCs, in comparison to deformable RBCs, quantitatively at physiological and above physiological flow shear stresses in blood samples obtained from SCD patients.”
“We observed significantly greater numbers of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.”
Now, the researchers are working to further characterize deformability and adhesion of RBCs in a greater number of SCD patients to analyze their associations with clinical phenotypes and complications.
The team said their system may provide important biophysical insights into disease pathophysiology when widely applied in SCD.
They also believe the microfluidic platform has the potential to be used as an in vitro assay for monitoring disease activity at baseline, during clinical flux after treatment, during painful episodes, and in association with long-term complications.
NICE recommends device for managing SCD
Image courtesy of Terumo BCT
The National Institute for Health and Care Excellence (NICE) has issued a guidance recommending a new device for managing sickle cell disease (SCD).
The device is the Spectra Optia Apheresis System for automated red blood cell (RBC) exchange in patients with SCD who need regular blood transfusions.
The Spectra Optia Apheresis System automatically replaces sickled RBCs with healthy RBCs.
The system is made up of 3 components: an apheresis machine, embedded software, and a single-use, disposable blood tubing set.
NICE said the Spectra Optia system is faster than manual RBC exchange, and patients need RBC exchange less often with this device. In addition, the system could provide considerable savings to the National Health Service (NHS) in England.
“The device could save the NHS in England an estimated £13 million each year—around £18,000 per patient—with the size of the saving depending on the patient’s condition and the equipment already owned by the NHS,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation.
“We also recommend that specialists collaborate to collect and publish data on some outcomes of treatment with Spectra Optia to provide further clinical evidence. It would be particularly helpful to have long-term data on how automated and manual exchange affects the amount of iron in the body and the need to treat this complication.”
Treatment with the Spectra Optia system is intended to be iron-neutral, meaning that patients who are already iron-overloaded can have their condition managed effectively.
The Spectra Optia Apheresis System is manufactured by Terumo BCT.
Costs and savings
The list prices (excluding tax) for the components of the Spectra Optia Apheresis System are as follows:
- Spectra Optia device: £45,350
- RBC exchange software: £6700
- Spectra Optia exchange set: £1007 per 6
- Astotube with injection port: £218 per 50
- ACD-A anticoagulant (750 ml): £57 per 12
- Service charge: £4572 per year.
Bulk order discounts are available.
Based on current evidence and expert advice on the anticipated benefits of the technology when used in patients with iron overload, cost modelling shows that, in most cases, using Spectra Optia is cost-saving compared with manual RBC exchange or top-up transfusion.
The savings depend on the iron overload status of the patient and are more likely to be achieved if devices already owned by the NHS can be used to treat SCD.
The estimated cost saving for adopting Spectra Optia is £18,100 per patient per year, which has the potential to save the NHS £12.9 million each year.
Image courtesy of Terumo BCT
The National Institute for Health and Care Excellence (NICE) has issued a guidance recommending a new device for managing sickle cell disease (SCD).
The device is the Spectra Optia Apheresis System for automated red blood cell (RBC) exchange in patients with SCD who need regular blood transfusions.
The Spectra Optia Apheresis System automatically replaces sickled RBCs with healthy RBCs.
The system is made up of 3 components: an apheresis machine, embedded software, and a single-use, disposable blood tubing set.
NICE said the Spectra Optia system is faster than manual RBC exchange, and patients need RBC exchange less often with this device. In addition, the system could provide considerable savings to the National Health Service (NHS) in England.
“The device could save the NHS in England an estimated £13 million each year—around £18,000 per patient—with the size of the saving depending on the patient’s condition and the equipment already owned by the NHS,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation.
“We also recommend that specialists collaborate to collect and publish data on some outcomes of treatment with Spectra Optia to provide further clinical evidence. It would be particularly helpful to have long-term data on how automated and manual exchange affects the amount of iron in the body and the need to treat this complication.”
Treatment with the Spectra Optia system is intended to be iron-neutral, meaning that patients who are already iron-overloaded can have their condition managed effectively.
The Spectra Optia Apheresis System is manufactured by Terumo BCT.
Costs and savings
The list prices (excluding tax) for the components of the Spectra Optia Apheresis System are as follows:
- Spectra Optia device: £45,350
- RBC exchange software: £6700
- Spectra Optia exchange set: £1007 per 6
- Astotube with injection port: £218 per 50
- ACD-A anticoagulant (750 ml): £57 per 12
- Service charge: £4572 per year.
Bulk order discounts are available.
Based on current evidence and expert advice on the anticipated benefits of the technology when used in patients with iron overload, cost modelling shows that, in most cases, using Spectra Optia is cost-saving compared with manual RBC exchange or top-up transfusion.
The savings depend on the iron overload status of the patient and are more likely to be achieved if devices already owned by the NHS can be used to treat SCD.
The estimated cost saving for adopting Spectra Optia is £18,100 per patient per year, which has the potential to save the NHS £12.9 million each year.
Image courtesy of Terumo BCT
The National Institute for Health and Care Excellence (NICE) has issued a guidance recommending a new device for managing sickle cell disease (SCD).
The device is the Spectra Optia Apheresis System for automated red blood cell (RBC) exchange in patients with SCD who need regular blood transfusions.
The Spectra Optia Apheresis System automatically replaces sickled RBCs with healthy RBCs.
The system is made up of 3 components: an apheresis machine, embedded software, and a single-use, disposable blood tubing set.
NICE said the Spectra Optia system is faster than manual RBC exchange, and patients need RBC exchange less often with this device. In addition, the system could provide considerable savings to the National Health Service (NHS) in England.
“The device could save the NHS in England an estimated £13 million each year—around £18,000 per patient—with the size of the saving depending on the patient’s condition and the equipment already owned by the NHS,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation.
“We also recommend that specialists collaborate to collect and publish data on some outcomes of treatment with Spectra Optia to provide further clinical evidence. It would be particularly helpful to have long-term data on how automated and manual exchange affects the amount of iron in the body and the need to treat this complication.”
Treatment with the Spectra Optia system is intended to be iron-neutral, meaning that patients who are already iron-overloaded can have their condition managed effectively.
The Spectra Optia Apheresis System is manufactured by Terumo BCT.
Costs and savings
The list prices (excluding tax) for the components of the Spectra Optia Apheresis System are as follows:
- Spectra Optia device: £45,350
- RBC exchange software: £6700
- Spectra Optia exchange set: £1007 per 6
- Astotube with injection port: £218 per 50
- ACD-A anticoagulant (750 ml): £57 per 12
- Service charge: £4572 per year.
Bulk order discounts are available.
Based on current evidence and expert advice on the anticipated benefits of the technology when used in patients with iron overload, cost modelling shows that, in most cases, using Spectra Optia is cost-saving compared with manual RBC exchange or top-up transfusion.
The savings depend on the iron overload status of the patient and are more likely to be achieved if devices already owned by the NHS can be used to treat SCD.
The estimated cost saving for adopting Spectra Optia is £18,100 per patient per year, which has the potential to save the NHS £12.9 million each year.
Transfusion doesn’t cause NEC, study suggests
Photo by Daniel Gay
Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.
Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.
But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.
So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.
To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.
The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).
Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).
The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.
However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).
On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).
The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.
However, such a strategy might impact other important neonatal outcomes, so further study is needed.
Photo by Daniel Gay
Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.
Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.
But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.
So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.
To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.
The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).
Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).
The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.
However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).
On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).
The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.
However, such a strategy might impact other important neonatal outcomes, so further study is needed.
Photo by Daniel Gay
Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.
Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.
But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.
So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.
To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.
The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).
Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).
The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.
However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).
On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).
The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.
However, such a strategy might impact other important neonatal outcomes, so further study is needed.
EC approves drug for iron-deficiency anemia in IBD
The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).
The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.
The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.
Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.
The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.
Phase 3 trials
The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.
Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.
The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).
The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.
The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.
AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.
“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.
“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’
The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).
The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.
The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.
Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.
The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.
Phase 3 trials
The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.
Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.
The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).
The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.
The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.
AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.
“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.
“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’
The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).
The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.
The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.
Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.
The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.
Phase 3 trials
The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.
Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.
The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).
The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.
The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.
AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.
“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.
“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’
Drug granted orphan designation for hemolytic anemia
The European Commission (EC) has granted orphan drug designation for TNT009 to treat autoimmune hemolytic anemia, including cold agglutinin disease.
TNT009 is a monoclonal antibody that selectively inhibits the classical complement pathway by targeting C1s, a serine protease within the C1-complex in the complement pathway.
The drug thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.
TNT009 is being developed by True North Therapeutics.
The drug is currently in development for the treatment of autoimmune hemolytic anemia, which is characterized by the premature destruction of healthy red blood cells by autoantibodies.
In cold agglutinin disease, this destruction of red blood cells results in anemia, fatigue, and potentially fatal thrombosis.
TNT009 is also being evaluated in patients with bullous pemphigoid and end-stage renal disease.
Top-line results from a phase 1b trial of TNT009 are expected in mid-2016.
About orphan designation
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.
Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.
The European Commission (EC) has granted orphan drug designation for TNT009 to treat autoimmune hemolytic anemia, including cold agglutinin disease.
TNT009 is a monoclonal antibody that selectively inhibits the classical complement pathway by targeting C1s, a serine protease within the C1-complex in the complement pathway.
The drug thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.
TNT009 is being developed by True North Therapeutics.
The drug is currently in development for the treatment of autoimmune hemolytic anemia, which is characterized by the premature destruction of healthy red blood cells by autoantibodies.
In cold agglutinin disease, this destruction of red blood cells results in anemia, fatigue, and potentially fatal thrombosis.
TNT009 is also being evaluated in patients with bullous pemphigoid and end-stage renal disease.
Top-line results from a phase 1b trial of TNT009 are expected in mid-2016.
About orphan designation
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.
Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.
The European Commission (EC) has granted orphan drug designation for TNT009 to treat autoimmune hemolytic anemia, including cold agglutinin disease.
TNT009 is a monoclonal antibody that selectively inhibits the classical complement pathway by targeting C1s, a serine protease within the C1-complex in the complement pathway.
The drug thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.
TNT009 is being developed by True North Therapeutics.
The drug is currently in development for the treatment of autoimmune hemolytic anemia, which is characterized by the premature destruction of healthy red blood cells by autoantibodies.
In cold agglutinin disease, this destruction of red blood cells results in anemia, fatigue, and potentially fatal thrombosis.
TNT009 is also being evaluated in patients with bullous pemphigoid and end-stage renal disease.
Top-line results from a phase 1b trial of TNT009 are expected in mid-2016.
About orphan designation
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.
Orphan drug designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is on the market.
Gene therapy could treat aplastic anemia
with telomeres in green
Image by Claus Azzalin
Researchers say they have found a new way to fight aplastic anemia—using a therapy designed to delay aging.
Four years ago, the group created telomerase gene therapy, an antiaging treatment based on repairing telomeres.
Now, they have found evidence to suggest this therapy can be effective against both acquired and inherited aplastic anemia.
The team reported preclinical results with the treatment in Blood.
In 2012, Maria A. Blasco, PhD, of Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, and her colleagues described a strategy to repair telomeres.
They used adeno-associated virus (AAV9) vectors to deliver telomerase (Tert) gene therapy, which attenuated or reverted aging-associated telomere erosion in peripheral blood mononuclear cells.
For the current study, the researchers tested the therapy in a mouse model of acquired aplastic anemia and one of inherited aplastic anemia.
Acquired aplastic anemia
For the model of acquired aplastic anemia, the researchers depleted the TRF1 shelterin protein in the bone marrow. The team said this causes severe telomere uncapping and provokes a persistent DNA damage response at telomeres, which leads to fast clearance of hematopoietic stem and progenitor cells (HSPCs) deficient for Trf1.
The remaining HSPCs then undergo additional rounds of compensatory proliferation to regenerate the bone marrow, which leads to rapid telomere attrition. So this model recapitulates the compensatory hyperproliferation and short-telomere phenotype observed in acquired aplastic anemia.
The researchers induced Trf1 deletion with polyinosinic-polycytidylic acid injections given 3 times a week for 5 weeks. At that point, the mice began to show signs of aplastic anemia. A week after the last injection, the mice received either AAV9-Tert or AAV9-empty vectors.
Eighty-seven percent of the AAV9-Tert mice were still alive at 100 days, compared to 55% of mice in the empty vector group (P=0.0025).
In addition, 13% (4/31) of the mice treated with AAV9-Tert actually developed aplastic anemia, while 44% (16/36) of the control mice died showing “clear signs” of aplastic anemia (P=0.0006).
Finally, the researchers found that AAV9-Tert reversed telomere shortening in peripheral blood and bone marrow cells.
Inherited aplastic anemia
For the model of inherited aplastic anemia, the researchers transplanted irradiated wild-type mice with bone marrow from third-generation telomerase-deficient Tert knockout mice. These mice have short telomeres resulting from telomerase deficiency over 3 generations.
As with the previous model, these mice received AAV9-Tert or AAV9-empty vectors. The AAV9-Tert mice had a superior survival rate that nearly reached statistical significance (P=0.058).
The researchers also found that, compared to controls, AAV9-Tert-treated mice had significant increases in hemoglobin levels (P=0.003), erythrocyte counts (P=0.006), and platelet counts (P=0.035), as well as a trend toward an increase in leukocyte counts (P=0.09).
In addition, AAV9-Tert treatment led to a net increase in average telomere length of 5.18Kb, while control mice had a slight telomere shortening of 1.76Kb.
The researchers noted that there are types of aplastic anemia not associated with short telomeres. However, they believe these results provide proof of concept that gene therapy is a valid strategy for treating aplastic anemia.
with telomeres in green
Image by Claus Azzalin
Researchers say they have found a new way to fight aplastic anemia—using a therapy designed to delay aging.
Four years ago, the group created telomerase gene therapy, an antiaging treatment based on repairing telomeres.
Now, they have found evidence to suggest this therapy can be effective against both acquired and inherited aplastic anemia.
The team reported preclinical results with the treatment in Blood.
In 2012, Maria A. Blasco, PhD, of Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, and her colleagues described a strategy to repair telomeres.
They used adeno-associated virus (AAV9) vectors to deliver telomerase (Tert) gene therapy, which attenuated or reverted aging-associated telomere erosion in peripheral blood mononuclear cells.
For the current study, the researchers tested the therapy in a mouse model of acquired aplastic anemia and one of inherited aplastic anemia.
Acquired aplastic anemia
For the model of acquired aplastic anemia, the researchers depleted the TRF1 shelterin protein in the bone marrow. The team said this causes severe telomere uncapping and provokes a persistent DNA damage response at telomeres, which leads to fast clearance of hematopoietic stem and progenitor cells (HSPCs) deficient for Trf1.
The remaining HSPCs then undergo additional rounds of compensatory proliferation to regenerate the bone marrow, which leads to rapid telomere attrition. So this model recapitulates the compensatory hyperproliferation and short-telomere phenotype observed in acquired aplastic anemia.
The researchers induced Trf1 deletion with polyinosinic-polycytidylic acid injections given 3 times a week for 5 weeks. At that point, the mice began to show signs of aplastic anemia. A week after the last injection, the mice received either AAV9-Tert or AAV9-empty vectors.
Eighty-seven percent of the AAV9-Tert mice were still alive at 100 days, compared to 55% of mice in the empty vector group (P=0.0025).
In addition, 13% (4/31) of the mice treated with AAV9-Tert actually developed aplastic anemia, while 44% (16/36) of the control mice died showing “clear signs” of aplastic anemia (P=0.0006).
Finally, the researchers found that AAV9-Tert reversed telomere shortening in peripheral blood and bone marrow cells.
Inherited aplastic anemia
For the model of inherited aplastic anemia, the researchers transplanted irradiated wild-type mice with bone marrow from third-generation telomerase-deficient Tert knockout mice. These mice have short telomeres resulting from telomerase deficiency over 3 generations.
As with the previous model, these mice received AAV9-Tert or AAV9-empty vectors. The AAV9-Tert mice had a superior survival rate that nearly reached statistical significance (P=0.058).
The researchers also found that, compared to controls, AAV9-Tert-treated mice had significant increases in hemoglobin levels (P=0.003), erythrocyte counts (P=0.006), and platelet counts (P=0.035), as well as a trend toward an increase in leukocyte counts (P=0.09).
In addition, AAV9-Tert treatment led to a net increase in average telomere length of 5.18Kb, while control mice had a slight telomere shortening of 1.76Kb.
The researchers noted that there are types of aplastic anemia not associated with short telomeres. However, they believe these results provide proof of concept that gene therapy is a valid strategy for treating aplastic anemia.
with telomeres in green
Image by Claus Azzalin
Researchers say they have found a new way to fight aplastic anemia—using a therapy designed to delay aging.
Four years ago, the group created telomerase gene therapy, an antiaging treatment based on repairing telomeres.
Now, they have found evidence to suggest this therapy can be effective against both acquired and inherited aplastic anemia.
The team reported preclinical results with the treatment in Blood.
In 2012, Maria A. Blasco, PhD, of Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, and her colleagues described a strategy to repair telomeres.
They used adeno-associated virus (AAV9) vectors to deliver telomerase (Tert) gene therapy, which attenuated or reverted aging-associated telomere erosion in peripheral blood mononuclear cells.
For the current study, the researchers tested the therapy in a mouse model of acquired aplastic anemia and one of inherited aplastic anemia.
Acquired aplastic anemia
For the model of acquired aplastic anemia, the researchers depleted the TRF1 shelterin protein in the bone marrow. The team said this causes severe telomere uncapping and provokes a persistent DNA damage response at telomeres, which leads to fast clearance of hematopoietic stem and progenitor cells (HSPCs) deficient for Trf1.
The remaining HSPCs then undergo additional rounds of compensatory proliferation to regenerate the bone marrow, which leads to rapid telomere attrition. So this model recapitulates the compensatory hyperproliferation and short-telomere phenotype observed in acquired aplastic anemia.
The researchers induced Trf1 deletion with polyinosinic-polycytidylic acid injections given 3 times a week for 5 weeks. At that point, the mice began to show signs of aplastic anemia. A week after the last injection, the mice received either AAV9-Tert or AAV9-empty vectors.
Eighty-seven percent of the AAV9-Tert mice were still alive at 100 days, compared to 55% of mice in the empty vector group (P=0.0025).
In addition, 13% (4/31) of the mice treated with AAV9-Tert actually developed aplastic anemia, while 44% (16/36) of the control mice died showing “clear signs” of aplastic anemia (P=0.0006).
Finally, the researchers found that AAV9-Tert reversed telomere shortening in peripheral blood and bone marrow cells.
Inherited aplastic anemia
For the model of inherited aplastic anemia, the researchers transplanted irradiated wild-type mice with bone marrow from third-generation telomerase-deficient Tert knockout mice. These mice have short telomeres resulting from telomerase deficiency over 3 generations.
As with the previous model, these mice received AAV9-Tert or AAV9-empty vectors. The AAV9-Tert mice had a superior survival rate that nearly reached statistical significance (P=0.058).
The researchers also found that, compared to controls, AAV9-Tert-treated mice had significant increases in hemoglobin levels (P=0.003), erythrocyte counts (P=0.006), and platelet counts (P=0.035), as well as a trend toward an increase in leukocyte counts (P=0.09).
In addition, AAV9-Tert treatment led to a net increase in average telomere length of 5.18Kb, while control mice had a slight telomere shortening of 1.76Kb.
The researchers noted that there are types of aplastic anemia not associated with short telomeres. However, they believe these results provide proof of concept that gene therapy is a valid strategy for treating aplastic anemia.