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Two activin receptor fusion proteins show promise in anemia
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.
Patients were a median age of 71, and 70% were male.
They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.
Sotatercept efficacy
The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.
Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.
Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.
Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.
Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.
Sotatercept safety
“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”
Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).
Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.
Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”
He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.
He presented the data as abstract 3251. The study was supported by Celgene Corporation. 
*One patient was excluded from the efficacy analysis due to a protocol violation.
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.
Patients were a median age of 71, and 70% were male.
They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.
Sotatercept efficacy
The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.
Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.
Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.
Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.
Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.
Sotatercept safety
“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”
Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).
Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.
Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”
He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.
He presented the data as abstract 3251. The study was supported by Celgene Corporation.
*One patient was excluded from the efficacy analysis due to a protocol violation.
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.
Patients were a median age of 71, and 70% were male.
They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.
Sotatercept efficacy
The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.
Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.
Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.
Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.
Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.
Sotatercept safety
“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”
Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).
Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.
Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”
He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.
He presented the data as abstract 3251. The study was supported by Celgene Corporation.
*One patient was excluded from the efficacy analysis due to a protocol violation.
Investigational sotatercept improves heme parameters in MDS
SAN FRANCISCO – A first-in-class investigational agent called sotatercept appears to be safe and to improve hematologic parameters in patients with lower-risk myelodysplastic syndrome or nonproliferative chronic myelomonocytic leukemia and anemia requiring transfusion, a study showed.
In the open-label phase II dose-finding study of sotatercept in patients with myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), hematologic improvement according to International Working Group (IWG) 2006 criteria was seen in 24 of 53 evaluable patients, said Dr. Rami Komrokji of the Moffitt Cancer Center,Tampa.
The patients were all refractory to, or were deemed to have a low chance of responding to, an erythropoiesis-stimulating agent (ESA), Dr. Komrokji said at the annual meeting of the American Society of Hematology.
“A medication like sotatercept would probably have a role in the management of anemia in lower-risk MDS patients. The treatment is administered every 3 weeks, which makes it also logistically easier for the patients to get the treatment. I don’t think we have seen any safety concern, at least at this point, about the chronic use of this medication,” he said in an interview.
Sotatercept (ACE-011) is an activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation. The mechanism of action is distinct from that of erythropoietins such as epoetin alfa (Procrit, Epogen) or darbapoietin alfa (Aranesp).
In clinical trials with healthy volunteers, sotatercept has been shown to increase hemoglobin levels, suggesting that it could help to reduce anemia and perhaps lessen dependence on transfusions among patients with lower-risk MDS, Dr. Komrokji said.
He and his colleagues at centers in the United States and France enrolled patients with low-risk or intermediate-1–risk MDS as defined by the International Prognostic Scoring System (IPSS), or nonproliferative CMML (fewer than 13,000 white blood cells per microliter). The patients had to have anemia requiring at least 2 red blood cell (RBC) transfusions in the 12 weeks before enrollment for hemoglobin levels below 9.0 g/dL, and no response, loss of response, or a low chance of response to an ESA. Those patients with serum erythropoietin levels greater than 500 mIU/mL were considered to have a low chance of responding to an ESA.
The patients received subcutaneous injections of sotatercept at doses of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks.
As noted, the rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation. Five of 44 patients with a high transfusion burden (4 or more RBC units required within 8 weeks) were able to be free of RBC transfusions for at least 8 weeks, as were 5 of 9 with a low transfusion burden (fewer than 4 RBC units over a period of 8 weeks).
Looking at the efficacy in patients with a high transfusion burden, the investigators found that 4 of 6 assigned to the 0.3-mg/kg dose group and 8 of 14 assigned to the 1-mg/kg dose group had a reduction in transfusion burden. The median duration of effect was 106 days, with the longest response lasting for 150 days.
There were no major adverse events in the study, and no apparent increase in risk for thrombosis, as had been seen in some studies of ESAs. Another theoretical risk with this type of agent is hypertension, but there was only one grade 3 case and no grade 4 cases of hypertension in the study, Dr. Komrokji said.
Sotatercept is currently in phase II trials for anemia related to hematologic malignancies and other diseases.
SAN FRANCISCO – A first-in-class investigational agent called sotatercept appears to be safe and to improve hematologic parameters in patients with lower-risk myelodysplastic syndrome or nonproliferative chronic myelomonocytic leukemia and anemia requiring transfusion, a study showed.
In the open-label phase II dose-finding study of sotatercept in patients with myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), hematologic improvement according to International Working Group (IWG) 2006 criteria was seen in 24 of 53 evaluable patients, said Dr. Rami Komrokji of the Moffitt Cancer Center,Tampa.
The patients were all refractory to, or were deemed to have a low chance of responding to, an erythropoiesis-stimulating agent (ESA), Dr. Komrokji said at the annual meeting of the American Society of Hematology.
“A medication like sotatercept would probably have a role in the management of anemia in lower-risk MDS patients. The treatment is administered every 3 weeks, which makes it also logistically easier for the patients to get the treatment. I don’t think we have seen any safety concern, at least at this point, about the chronic use of this medication,” he said in an interview.
Sotatercept (ACE-011) is an activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation. The mechanism of action is distinct from that of erythropoietins such as epoetin alfa (Procrit, Epogen) or darbapoietin alfa (Aranesp).
In clinical trials with healthy volunteers, sotatercept has been shown to increase hemoglobin levels, suggesting that it could help to reduce anemia and perhaps lessen dependence on transfusions among patients with lower-risk MDS, Dr. Komrokji said.
He and his colleagues at centers in the United States and France enrolled patients with low-risk or intermediate-1–risk MDS as defined by the International Prognostic Scoring System (IPSS), or nonproliferative CMML (fewer than 13,000 white blood cells per microliter). The patients had to have anemia requiring at least 2 red blood cell (RBC) transfusions in the 12 weeks before enrollment for hemoglobin levels below 9.0 g/dL, and no response, loss of response, or a low chance of response to an ESA. Those patients with serum erythropoietin levels greater than 500 mIU/mL were considered to have a low chance of responding to an ESA.
The patients received subcutaneous injections of sotatercept at doses of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks.
As noted, the rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation. Five of 44 patients with a high transfusion burden (4 or more RBC units required within 8 weeks) were able to be free of RBC transfusions for at least 8 weeks, as were 5 of 9 with a low transfusion burden (fewer than 4 RBC units over a period of 8 weeks).
Looking at the efficacy in patients with a high transfusion burden, the investigators found that 4 of 6 assigned to the 0.3-mg/kg dose group and 8 of 14 assigned to the 1-mg/kg dose group had a reduction in transfusion burden. The median duration of effect was 106 days, with the longest response lasting for 150 days.
There were no major adverse events in the study, and no apparent increase in risk for thrombosis, as had been seen in some studies of ESAs. Another theoretical risk with this type of agent is hypertension, but there was only one grade 3 case and no grade 4 cases of hypertension in the study, Dr. Komrokji said.
Sotatercept is currently in phase II trials for anemia related to hematologic malignancies and other diseases.
SAN FRANCISCO – A first-in-class investigational agent called sotatercept appears to be safe and to improve hematologic parameters in patients with lower-risk myelodysplastic syndrome or nonproliferative chronic myelomonocytic leukemia and anemia requiring transfusion, a study showed.
In the open-label phase II dose-finding study of sotatercept in patients with myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), hematologic improvement according to International Working Group (IWG) 2006 criteria was seen in 24 of 53 evaluable patients, said Dr. Rami Komrokji of the Moffitt Cancer Center,Tampa.
The patients were all refractory to, or were deemed to have a low chance of responding to, an erythropoiesis-stimulating agent (ESA), Dr. Komrokji said at the annual meeting of the American Society of Hematology.
“A medication like sotatercept would probably have a role in the management of anemia in lower-risk MDS patients. The treatment is administered every 3 weeks, which makes it also logistically easier for the patients to get the treatment. I don’t think we have seen any safety concern, at least at this point, about the chronic use of this medication,” he said in an interview.
Sotatercept (ACE-011) is an activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation. The mechanism of action is distinct from that of erythropoietins such as epoetin alfa (Procrit, Epogen) or darbapoietin alfa (Aranesp).
In clinical trials with healthy volunteers, sotatercept has been shown to increase hemoglobin levels, suggesting that it could help to reduce anemia and perhaps lessen dependence on transfusions among patients with lower-risk MDS, Dr. Komrokji said.
He and his colleagues at centers in the United States and France enrolled patients with low-risk or intermediate-1–risk MDS as defined by the International Prognostic Scoring System (IPSS), or nonproliferative CMML (fewer than 13,000 white blood cells per microliter). The patients had to have anemia requiring at least 2 red blood cell (RBC) transfusions in the 12 weeks before enrollment for hemoglobin levels below 9.0 g/dL, and no response, loss of response, or a low chance of response to an ESA. Those patients with serum erythropoietin levels greater than 500 mIU/mL were considered to have a low chance of responding to an ESA.
The patients received subcutaneous injections of sotatercept at doses of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks.
As noted, the rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation. Five of 44 patients with a high transfusion burden (4 or more RBC units required within 8 weeks) were able to be free of RBC transfusions for at least 8 weeks, as were 5 of 9 with a low transfusion burden (fewer than 4 RBC units over a period of 8 weeks).
Looking at the efficacy in patients with a high transfusion burden, the investigators found that 4 of 6 assigned to the 0.3-mg/kg dose group and 8 of 14 assigned to the 1-mg/kg dose group had a reduction in transfusion burden. The median duration of effect was 106 days, with the longest response lasting for 150 days.
There were no major adverse events in the study, and no apparent increase in risk for thrombosis, as had been seen in some studies of ESAs. Another theoretical risk with this type of agent is hypertension, but there was only one grade 3 case and no grade 4 cases of hypertension in the study, Dr. Komrokji said.
Sotatercept is currently in phase II trials for anemia related to hematologic malignancies and other diseases.
Key clinical point: Sotatercept is a first-in-its-class agent that stimulates erythropoiesis through a mechanism different from that of erythropoietins.
Major finding: The rate of overall hematologic improvement by IWG 2006 criteria was 45%, occurring in 24 of 53 patients available for evaluation.
Data source: An ongoing phase II study with data available on 53 patients with MDS or nonproliferative CMML.
Disclosures: The study is sponsored by Celgene. Dr. Komrokji reported consulting for and receiving research funding from the company.
Vitiligo, alopecia more likely in GVHD when donor is female and recipient is male
The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.
Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.
They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.
"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.
In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).
Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.
This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.
The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.
Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.
They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.
"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.
In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).
Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.
This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.
The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.
Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.
They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.
"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.
In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).
Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.
This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.
FROM JAMA DERMATOLOGY
Key clinical point: Female-to-male stem cell donation ups the risk for vitiligo in GVHD.
Major finding: 14 of the 15 patients who developed vitiligo or alopecia areata had female donors (the gender of the 15th donor was unknown), and 9 of these 14 recipients were male.
Data source: A retrospective cross-sectional analysis involving 282 adults and children with chronic GVHD, 15 of whom developed vitiligo or alopecia areata.
Disclosures: This study was supported by the National Institutes of Health and the National Cancer Institute. Dr. Zuo and her associates reported no financial conflicts of interest.
FDA approves generic decitabine for MDS
Credit: Bill Branson
The US Food and Drug Administration (FDA) has approved decitabine for injection, a generic version of Dacogen, to treat patients with myelodysplastic syndromes (MDS).
Decitabine is indicated for previously treated and untreated patients with de novo and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia—as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
Decitabine will be marketed in 20 mL single-dose glass vials containing 50 mg decitabine—the same size and strength as the brand name drug. The dosing regimen is identical as well.
InnoPharma developed the generic formulation of decitabine and entered into an agreement with Sandoz Inc. Sandoz will sell, market, and distribute decitabine in the US. InnoPharma is set to be acquired by Pfizer Inc., but the transaction is subject to US regulatory approval.
The FDA approved another generic form of decitabine for the treatment of MDS in July 2013. That drug is a product of Dr Reddy’s Laboratories Limited.
Dacogen has been FDA-approved to treat MDS since May 2006. Dacogen is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals Inc. 
Credit: Bill Branson
The US Food and Drug Administration (FDA) has approved decitabine for injection, a generic version of Dacogen, to treat patients with myelodysplastic syndromes (MDS).
Decitabine is indicated for previously treated and untreated patients with de novo and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia—as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
Decitabine will be marketed in 20 mL single-dose glass vials containing 50 mg decitabine—the same size and strength as the brand name drug. The dosing regimen is identical as well.
InnoPharma developed the generic formulation of decitabine and entered into an agreement with Sandoz Inc. Sandoz will sell, market, and distribute decitabine in the US. InnoPharma is set to be acquired by Pfizer Inc., but the transaction is subject to US regulatory approval.
The FDA approved another generic form of decitabine for the treatment of MDS in July 2013. That drug is a product of Dr Reddy’s Laboratories Limited.
Dacogen has been FDA-approved to treat MDS since May 2006. Dacogen is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals Inc.
Credit: Bill Branson
The US Food and Drug Administration (FDA) has approved decitabine for injection, a generic version of Dacogen, to treat patients with myelodysplastic syndromes (MDS).
Decitabine is indicated for previously treated and untreated patients with de novo and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia—as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
Decitabine will be marketed in 20 mL single-dose glass vials containing 50 mg decitabine—the same size and strength as the brand name drug. The dosing regimen is identical as well.
InnoPharma developed the generic formulation of decitabine and entered into an agreement with Sandoz Inc. Sandoz will sell, market, and distribute decitabine in the US. InnoPharma is set to be acquired by Pfizer Inc., but the transaction is subject to US regulatory approval.
The FDA approved another generic form of decitabine for the treatment of MDS in July 2013. That drug is a product of Dr Reddy’s Laboratories Limited.
Dacogen has been FDA-approved to treat MDS since May 2006. Dacogen is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals Inc.
Drugs can increase risk of MDS and AML
A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).
In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.
However, the absolute risk to an individual patient was about 1 in 10,000.
The researchers reported these results in Clinical Gastroenterology and Hepatology.
Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.
Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.
“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.
“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”
The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.
At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.
After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.
The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.
Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.
However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.
The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.
So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.
The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.
A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).
In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.
However, the absolute risk to an individual patient was about 1 in 10,000.
The researchers reported these results in Clinical Gastroenterology and Hepatology.
Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.
Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.
“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.
“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”
The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.
At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.
After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.
The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.
Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.
However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.
The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.
So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.
The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.
A class of immunosuppressive agents appear to increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with inflammatory bowel disease (IBD).
In an observational study of more than 19,000 IBD patients, past exposure to the agents—thiopurines—increased the risk of developing AML or MDS nearly 7-fold, when compared to the general population.
However, the absolute risk to an individual patient was about 1 in 10,000.
The researchers reported these results in Clinical Gastroenterology and Hepatology.
Thiopurines are an established treatment for IBD patients, but the drugs are also used to prevent rejection after a kidney transplant, to treat rheumatoid arthritis, as maintenance therapy for acute lymphocytic leukemia, and to induce remission in patients with AML.
Previous research showed that long-term use of thiopurines can increase a person’s risk of developing lymphoma.
“In order to make appropriate, informed decisions about thiopurines, patients and providers need to be well-educated about the risks and benefits of this treatment,” said study author Laurent Peyrin-Biroulet, MD, PhD, of the University Hospital of Nancy-Brabois in France.
“According to our research, the risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. However, it was increased amongst those taking thiopurines. We hope these findings encourage other researchers to investigate more about the drug and its potentially harmful effects.”
The researchers analyzed 19,486 patients who were enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France study from May 2004 through June 2005.
At study entry, 10,810 patients had never received thiopurines, 2810 patients had discontinued such drugs, and 5866 patients were still receiving them.
After 3 years of follow up, 5 patients were diagnosed with incident myeloid disorders—2 with AML and 3 with MDS. Four of these patients had been exposed to thiopurines—1 with ongoing treatment and 3 with past exposure.
The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population. The standardized incidence ratio (SIR) was 1.80.
Similarly, the risk of myeloid disorders was not increased among IBD patients still receiving thiopurine treatment. The SIR was 1.54.
However, patients with prior exposure to thiopurines did have a significantly increased risk of myeloid disorders, with an SIR of 6.98.
The researchers noted that, although these findings provide evidence of a connection between thiopurines and myeloid disorders in IBD patients, the absolute risk to an individual patient was low.
So it seems the link between thiopurines and myeloid disorders remains complex. And physicians must balance the risk against the known benefits of thiopurines in the management of IBD.
The American Gastroenterological Association has developed a guideline-based clinical decision support tool to help providers determine when to use thiopurines in these patients.
AG-221 sparked durable responses in hematologic cancers
MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.
Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.
Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.
Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.
"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.
AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).
About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.
An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.
Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.
Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.
Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.
AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.
The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.
Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.
There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.
There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.
"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.
Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.
MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.
Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.
Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.
Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.
"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.
AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).
About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.
An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.
Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.
Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.
Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.
AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.
The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.
Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.
There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.
There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.
"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.
Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.
MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.
Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.
Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.
Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.
"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.
AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).
About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.
An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.
Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.
Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.
Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.
AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.
The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.
Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.
There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.
There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.
"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.
Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.
AT THE EHA CONGRESS
Key clinical point: AG-221 could shift the treatment for IDH2 mutation-positive hematologic cancers.
Major finding: Fourteen of 25 patients responded to treatment with AG-221.
Data source: A prospective phase I dose-escalation study in 35 patients with hematologic cancers.
Disclosures: Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.
Inhibitor shows promise for hematologic disorders
Photo courtesy of EHA
MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.
The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).
Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.
Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.
Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.
Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).
Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.
The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.
Safety data
“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”
Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).
Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.
Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.
Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.
Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.
Activity and response data
The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.
He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.
Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).
In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).
The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.
“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”
Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.
This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.
Photo courtesy of EHA
MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.
The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).
Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.
Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.
Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.
Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).
Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.
The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.
Safety data
“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”
Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).
Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.
Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.
Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.
Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.
Activity and response data
The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.
He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.
Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).
In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).
The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.
“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”
Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.
This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.
Photo courtesy of EHA
MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.
The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).
Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.
Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.
Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.
Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).
Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.
The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.
Safety data
“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”
Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).
Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.
Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.
Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.
Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.
Activity and response data
The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.
He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.
Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).
In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).
The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.
“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”
Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.
This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.
Group finds cancer stem cells in MDS patients
Credit: NIH
A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.
The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.
Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.
The researchers reported these discoveries in Cancer Cell.
Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.
The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin-CD34+CD38-CD90+CD45RA- cells—that appeared to have all the properties of cancer stem cells.
These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.
“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”
Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.
But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.
“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.
Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.
“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”
Credit: NIH
A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.
The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.
Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.
The researchers reported these discoveries in Cancer Cell.
Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.
The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin-CD34+CD38-CD90+CD45RA- cells—that appeared to have all the properties of cancer stem cells.
These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.
“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”
Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.
But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.
“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.
Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.
“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”
Credit: NIH
A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.
The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.
Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.
The researchers reported these discoveries in Cancer Cell.
Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.
The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin-CD34+CD38-CD90+CD45RA- cells—that appeared to have all the properties of cancer stem cells.
These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.
“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”
Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.
But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.
“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.
Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.
“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”
Testing reveals abnormalities in CN-AML/MDS
Credit: NIGMS
NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).
Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.
The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.
This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.
“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”
Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.
He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.
The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.
According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.
For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.
Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.
SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.
The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.
The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.
Credit: NIGMS
NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).
Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.
The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.
This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.
“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”
Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.
He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.
The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.
According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.
For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.
Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.
SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.
The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.
The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.
Credit: NIGMS
NASHVILLE—New research suggests we may need to use more sensitive methods to analyze patients with cytogenetically normal acute myeloid leukemia or myelodysplastic syndrome (CN-AML/MDS).
Using “highly sensitive” microarray technology, researchers found a distinct pattern of genetic abnormalities in 22 patients diagnosed with CN-AML/MDS.
The team identified 3 overlapping regions of homozygosity in 3 genes, 2 of which are known to be involved in carcinogenesis.
This suggests that using karyotyping or FISH, or simply looking for known mutations, is not sufficient for evaluating patients with CN-AML/MDS, according to Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Georgia Regents University.
“The technology we currently use can’t identify specifically what’s wrong,” Dr Kolhe said. “We have to use more sensitive tests to give patients the proper answer.”
Dr Kolhe presented this finding, and the research to support it, at the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting.
He and his colleagues analyzed 22 patients. Seventeen had AML, and 5 had MDS, including 1 with refractory anemia with excess blasts-2. All patients had normal karyotype and FISH and had greater than 20% blasts in the bone marrow.
The researchers analyzed samples from these patients using a high-resolution, single-nucleotide polymorphism (SNP) microarray called CytoScanHD.
According to the company that markets this technology (Affymetrix, Inc.), the assay includes 750,000 SNPs with over 99% accuracy to detect accurate breakpoint estimation, loss of heterozygosity determination, regions identical-by-descent, maternal contamination, and low-level mosaicism.
For Dr Kolhe and his colleagues, the assay revealed small, previously undetectable changes in patients thought to be cytogenetically normal.
Specifically, the researchers identified 3 overlapping regions of homozygosity in all 22 cases—chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 in the SFPQ, EPS15, and CTCF genes, respectively.
SFPQ and CTCF are already known to be involved in carcinogenesis, and Dr Kolhe and his colleagues are now investigating the role of EPS15 in leukemogenesis.
The researchers also identified additional abnormalities and are investigating these as well. They are sequencing the genes to identify homozygous or compound heterozygous mutations, performing expression studies to confirm that these mutations are leukemic, and conducting experiments in knockout mice to demonstrate that these genes produce the same leukemia phenotype.
The materials and reagents for this study were provided by Affymetrix. The test design, experimentation, data collection, analysis, and interpretation were done independently by the researchers.
Monosomal karyotype, high prognostic risk score predicted transplantation failure
Monosomal karyotype and high prognostic risk according to the revised International Prognostic Scoring System are independent predictors of relapse and mortality in patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who undergo allogeneic hematopoietic stem cell transplantation, according to findings from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) registry.
Treatment failure after allogeneic hematopoietic stem cell transplantation may be from transplant complications or relapse. To understand the predictors of failure, investigators studied outcomes in 519 patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who underwent hematopoietic stem cell transplantation between 2000 and 2011.
Those with monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate; both rates were significantly worse, compared with patients without monosomal karyotype (P less than .001 for each). Those considered high or very-high risk based on the International Prognostic Scoring System (IPSS-R), had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively (P less than .001 in all cases vs. patients not at high or very-high risk), Dr. Matteo G. Della Porta of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and colleagues reported on behalf of the GITMO.
Age of 50 years or older and high hematopoietic cell transplantation-comorbidity index scores were independent predictors of nonrelapse mortality (P = .02; P = .017, respectively), they found (Blood 2014 [doi:10.1182/blood-2013-12-542720]).
Accounting for various combinations of patients’ ages, IPSS-R category, monosomal karyotype, and high hematopoietic cell transplantation–comorbidity index, the 5-year probability of survival after allogeneic hematopoietic stem cell transplantation ranged from 0 to 94%. The analyses performed reinforce the concept that allogenic hematopoietic stem cell transplantation – the only potentially curative treatment for MDS – "offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages," the investigators concluded.
The investigators reported having no disclosures.
Monosomal karyotype and high prognostic risk according to the revised International Prognostic Scoring System are independent predictors of relapse and mortality in patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who undergo allogeneic hematopoietic stem cell transplantation, according to findings from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) registry.
Treatment failure after allogeneic hematopoietic stem cell transplantation may be from transplant complications or relapse. To understand the predictors of failure, investigators studied outcomes in 519 patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who underwent hematopoietic stem cell transplantation between 2000 and 2011.
Those with monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate; both rates were significantly worse, compared with patients without monosomal karyotype (P less than .001 for each). Those considered high or very-high risk based on the International Prognostic Scoring System (IPSS-R), had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively (P less than .001 in all cases vs. patients not at high or very-high risk), Dr. Matteo G. Della Porta of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and colleagues reported on behalf of the GITMO.
Age of 50 years or older and high hematopoietic cell transplantation-comorbidity index scores were independent predictors of nonrelapse mortality (P = .02; P = .017, respectively), they found (Blood 2014 [doi:10.1182/blood-2013-12-542720]).
Accounting for various combinations of patients’ ages, IPSS-R category, monosomal karyotype, and high hematopoietic cell transplantation–comorbidity index, the 5-year probability of survival after allogeneic hematopoietic stem cell transplantation ranged from 0 to 94%. The analyses performed reinforce the concept that allogenic hematopoietic stem cell transplantation – the only potentially curative treatment for MDS – "offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages," the investigators concluded.
The investigators reported having no disclosures.
Monosomal karyotype and high prognostic risk according to the revised International Prognostic Scoring System are independent predictors of relapse and mortality in patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who undergo allogeneic hematopoietic stem cell transplantation, according to findings from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) registry.
Treatment failure after allogeneic hematopoietic stem cell transplantation may be from transplant complications or relapse. To understand the predictors of failure, investigators studied outcomes in 519 patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who underwent hematopoietic stem cell transplantation between 2000 and 2011.
Those with monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate; both rates were significantly worse, compared with patients without monosomal karyotype (P less than .001 for each). Those considered high or very-high risk based on the International Prognostic Scoring System (IPSS-R), had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively (P less than .001 in all cases vs. patients not at high or very-high risk), Dr. Matteo G. Della Porta of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and colleagues reported on behalf of the GITMO.
Age of 50 years or older and high hematopoietic cell transplantation-comorbidity index scores were independent predictors of nonrelapse mortality (P = .02; P = .017, respectively), they found (Blood 2014 [doi:10.1182/blood-2013-12-542720]).
Accounting for various combinations of patients’ ages, IPSS-R category, monosomal karyotype, and high hematopoietic cell transplantation–comorbidity index, the 5-year probability of survival after allogeneic hematopoietic stem cell transplantation ranged from 0 to 94%. The analyses performed reinforce the concept that allogenic hematopoietic stem cell transplantation – the only potentially curative treatment for MDS – "offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages," the investigators concluded.
The investigators reported having no disclosures.
FROM BLOOD
Major finding: Patients with a monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate, and those considered high or very-high risk based on the IPSS-R, had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively.
Data source: An analysis of GITMO registry data.
Disclosures: The investigators reported having no disclosures.