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CHMP supports expanded approval for epoetin alfa products
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.
The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of the CHMP’s recommendation.
Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:
- To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
- To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
- For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
- For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
- For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.
The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of the CHMP’s recommendation.
Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:
- To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
- To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
- For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
- For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
- For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.
The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of the CHMP’s recommendation.
Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:
- To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
- To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
- For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
- For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
- For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.
Study could change treatment of MLSM7
New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.
While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).
However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.
The team recounted these findings in JCI Insight.
The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.
“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.
The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.
Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.
“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”
Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.
In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.
Implications for treatment
This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.
These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.
The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.
For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.
“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”
“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”
New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.
While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).
However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.
The team recounted these findings in JCI Insight.
The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.
“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.
The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.
Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.
“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”
Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.
In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.
Implications for treatment
This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.
These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.
The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.
For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.
“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”
“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”
New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.
While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).
However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.
The team recounted these findings in JCI Insight.
The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.
“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.
The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.
Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.
“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”
Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.
In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.
Implications for treatment
This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.
These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.
The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.
For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.
“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”
“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”
Treatments, disease affect spermatogonia in boys
Alkylating agents, hydroxyurea (HU), and certain non-malignant diseases can significantly deplete spermatogonial cell counts in young boys, according to research published in Human Reproduction.
Boys who received alkylating agents to treat cancer had significantly lower spermatogonial cell counts than control subjects or boys with malignant/nonmalignant diseases treated with non-alkylating agents.
Five of 6 SCD patients treated with HU had a totally depleted spermatogonial pool, and the remaining patient had a low spermatogonial cell count.
Five boys with non-malignant diseases who were not exposed to chemotherapy had significantly lower spermatogonial cell counts than controls.
“Our findings of a dramatic decrease in germ cell numbers in boys treated with alkylating agents and in sickle cell disease patients treated with hydroxyurea suggest that storing frozen testicular tissue from these boys should be performed before these treatments are initiated,” said study author Cecilia Petersen, MD, PhD, of Karolinska Institutet and University Hospital in Stockholm, Sweden.
“This needs to be communicated to physicians as well as patients and their parents or carers. However, until sperm that are able to fertilize eggs are produced from stored testicular tissue, we cannot confirm that germ cell quantity might determine the success of transplantation of the tissue in adulthood. Further research on this is needed to establish a realistic fertility preservation technique.”
Dr Petersen and her colleagues also noted that preserving testicular tissue may not be a viable option for boys who have low spermatogonial cell counts prior to treatment.
Patients and controls
For this study, the researchers analyzed testicular tissue from 32 boys facing treatments that carried a high risk of infertility—testicular irradiation, chemotherapy, or radiotherapy in advance of stem cell transplant.
Twenty boys had the tissue taken after initial chemotherapy, and 12 had it taken before starting any treatment.1
Eight patients had received chemotherapy with non-alkylating agents, 6 (all with malignancies) had received alkylating agents, and 6 (all with SCD) had received HU.
Diseases included acute lymphoblastic leukemia (n=6), SCD (n=6), acute myeloid leukemia (n=3), thalassemia major (n=3), neuroblastoma (n=2), juvenile myelomonocytic leukemia (n=2), myelodysplastic syndromes (n=2), primary immunodeficiency (n=2), Wilms tumor (n=1), adrenoleukodystrophy (n=1), hepatoblastoma (n=1), primitive neuroectodermal tumor (n=1), severe aplastic anemia (n=1), and Fanconi anemia (n=1).
The researchers compared samples from these 32 patients to 14 healthy testicular tissue samples stored in the biobank at the Karolinska University Hospital.
For both sample types, the team counted the number of spermatogonial cells found in a cross-section of seminiferous tubules.
“We could compare the number of spermatogonia with those found in the healthy boys as a way to estimate the effect of medical treatment or the disease itself on the future fertility of a patient,” explained study author Jan-Bernd Stukenborg, PhD, of Karolinska Institutet and University Hospital.
Impact of treatment
There was no significant difference in the mean quantity of spermatogonia per transverse tubular cross-section (S/T) between patients exposed to non-alkylating agents (1.7 ± 1.0, n=8) and biobank controls (4.1 ± 4.6, n=14).
However, samples from patients who received alkylating agents had a significantly lower mean S/T value (0.2 ± 0.3, n=6) than samples from patients treated with non-alkylating agents (P=0.003) and biobank controls (P<0.001).
“We found that the numbers of germ cells present in the cross-sections of the seminiferous tubules were significantly depleted and close to 0 in patients treated with alkylating agents,” Dr Stukenborg said.
Samples from the SCD patients also had a significantly lower mean S/T value (0.3 ± 0.6, n=6) than biobank controls (P=0.003).
Dr Stukenborg noted that the germ cell pool was totally depleted in 5 of the boys with SCD, and the pool was “very low” in the sixth SCD patient.
“This was not seen in patients who had not started treatment or were treated with non-alkylating agents or in the biobank tissues,” Dr Stukenborg said.2
He and his colleagues noted that it is possible for germ cells to recover to normal levels after treatment that is highly toxic to the testes, but high doses of alkylating agents and radiotherapy to the testicles are strongly associated with permanent or long-term infertility.
“The first group of boys who received bone marrow transplants are now reaching their thirties,” said study author Kirsi Jahnukainen, MD, PhD, of Helsinki University Central Hospital in Finland.
“Recent data suggest they may have a high chance of their sperm production recovering, even if they received high-dose alkylating therapies, so long as they had no testicular irradiation.”
Impact of disease
The researchers also found evidence to suggest that, for some boys, their disease may have affected spermatogonial cell counts before any treatment began.
Five patients with non-malignant disease who had not been exposed to chemotherapy (3 with thalassemia major, 1 with Fanconi anemia, and 1 with primary immunodeficiency) had a significantly lower mean S/T value (0.4 ± 0.5) than controls (P=0.006).
“Among patients who had not been treated previously with chemotherapy, there were several boys with a low number of germ cells for their age,” Dr Jahnukainen said.
“This suggests that some non-malignant diseases that require bone marrow transplants may affect the fertility of young boys even before exposure to therapy that is toxic for the testes.”
The researchers noted that a limitation of this study was that biobank samples had no detailed information regarding previous medical treatments and testicular volumes.
1. Testicular tissue is taken from patients under general anesthesia. The surgeon removes approximately 20% of the tissue from the testicular capsule in one of the testicles. For this study, a third of the tissue was taken to the Karolinska Institutet for analysis.
2. A recent meta-analysis showed that normal testicular tissue samples of newborns contain approximately 2.5 germ cells per tubular cross-section. This number decreases to approximately 1.2 within the first 3 years of age, followed by an increase up to 2.6 germ cells per tubular cross-section at 6 to 7 years, reaching a plateau until the age of 11. At the onset of puberty, an increase of up to 7 spermatogonia per tubular cross-section could be observed.
Alkylating agents, hydroxyurea (HU), and certain non-malignant diseases can significantly deplete spermatogonial cell counts in young boys, according to research published in Human Reproduction.
Boys who received alkylating agents to treat cancer had significantly lower spermatogonial cell counts than control subjects or boys with malignant/nonmalignant diseases treated with non-alkylating agents.
Five of 6 SCD patients treated with HU had a totally depleted spermatogonial pool, and the remaining patient had a low spermatogonial cell count.
Five boys with non-malignant diseases who were not exposed to chemotherapy had significantly lower spermatogonial cell counts than controls.
“Our findings of a dramatic decrease in germ cell numbers in boys treated with alkylating agents and in sickle cell disease patients treated with hydroxyurea suggest that storing frozen testicular tissue from these boys should be performed before these treatments are initiated,” said study author Cecilia Petersen, MD, PhD, of Karolinska Institutet and University Hospital in Stockholm, Sweden.
“This needs to be communicated to physicians as well as patients and their parents or carers. However, until sperm that are able to fertilize eggs are produced from stored testicular tissue, we cannot confirm that germ cell quantity might determine the success of transplantation of the tissue in adulthood. Further research on this is needed to establish a realistic fertility preservation technique.”
Dr Petersen and her colleagues also noted that preserving testicular tissue may not be a viable option for boys who have low spermatogonial cell counts prior to treatment.
Patients and controls
For this study, the researchers analyzed testicular tissue from 32 boys facing treatments that carried a high risk of infertility—testicular irradiation, chemotherapy, or radiotherapy in advance of stem cell transplant.
Twenty boys had the tissue taken after initial chemotherapy, and 12 had it taken before starting any treatment.1
Eight patients had received chemotherapy with non-alkylating agents, 6 (all with malignancies) had received alkylating agents, and 6 (all with SCD) had received HU.
Diseases included acute lymphoblastic leukemia (n=6), SCD (n=6), acute myeloid leukemia (n=3), thalassemia major (n=3), neuroblastoma (n=2), juvenile myelomonocytic leukemia (n=2), myelodysplastic syndromes (n=2), primary immunodeficiency (n=2), Wilms tumor (n=1), adrenoleukodystrophy (n=1), hepatoblastoma (n=1), primitive neuroectodermal tumor (n=1), severe aplastic anemia (n=1), and Fanconi anemia (n=1).
The researchers compared samples from these 32 patients to 14 healthy testicular tissue samples stored in the biobank at the Karolinska University Hospital.
For both sample types, the team counted the number of spermatogonial cells found in a cross-section of seminiferous tubules.
“We could compare the number of spermatogonia with those found in the healthy boys as a way to estimate the effect of medical treatment or the disease itself on the future fertility of a patient,” explained study author Jan-Bernd Stukenborg, PhD, of Karolinska Institutet and University Hospital.
Impact of treatment
There was no significant difference in the mean quantity of spermatogonia per transverse tubular cross-section (S/T) between patients exposed to non-alkylating agents (1.7 ± 1.0, n=8) and biobank controls (4.1 ± 4.6, n=14).
However, samples from patients who received alkylating agents had a significantly lower mean S/T value (0.2 ± 0.3, n=6) than samples from patients treated with non-alkylating agents (P=0.003) and biobank controls (P<0.001).
“We found that the numbers of germ cells present in the cross-sections of the seminiferous tubules were significantly depleted and close to 0 in patients treated with alkylating agents,” Dr Stukenborg said.
Samples from the SCD patients also had a significantly lower mean S/T value (0.3 ± 0.6, n=6) than biobank controls (P=0.003).
Dr Stukenborg noted that the germ cell pool was totally depleted in 5 of the boys with SCD, and the pool was “very low” in the sixth SCD patient.
“This was not seen in patients who had not started treatment or were treated with non-alkylating agents or in the biobank tissues,” Dr Stukenborg said.2
He and his colleagues noted that it is possible for germ cells to recover to normal levels after treatment that is highly toxic to the testes, but high doses of alkylating agents and radiotherapy to the testicles are strongly associated with permanent or long-term infertility.
“The first group of boys who received bone marrow transplants are now reaching their thirties,” said study author Kirsi Jahnukainen, MD, PhD, of Helsinki University Central Hospital in Finland.
“Recent data suggest they may have a high chance of their sperm production recovering, even if they received high-dose alkylating therapies, so long as they had no testicular irradiation.”
Impact of disease
The researchers also found evidence to suggest that, for some boys, their disease may have affected spermatogonial cell counts before any treatment began.
Five patients with non-malignant disease who had not been exposed to chemotherapy (3 with thalassemia major, 1 with Fanconi anemia, and 1 with primary immunodeficiency) had a significantly lower mean S/T value (0.4 ± 0.5) than controls (P=0.006).
“Among patients who had not been treated previously with chemotherapy, there were several boys with a low number of germ cells for their age,” Dr Jahnukainen said.
“This suggests that some non-malignant diseases that require bone marrow transplants may affect the fertility of young boys even before exposure to therapy that is toxic for the testes.”
The researchers noted that a limitation of this study was that biobank samples had no detailed information regarding previous medical treatments and testicular volumes.
1. Testicular tissue is taken from patients under general anesthesia. The surgeon removes approximately 20% of the tissue from the testicular capsule in one of the testicles. For this study, a third of the tissue was taken to the Karolinska Institutet for analysis.
2. A recent meta-analysis showed that normal testicular tissue samples of newborns contain approximately 2.5 germ cells per tubular cross-section. This number decreases to approximately 1.2 within the first 3 years of age, followed by an increase up to 2.6 germ cells per tubular cross-section at 6 to 7 years, reaching a plateau until the age of 11. At the onset of puberty, an increase of up to 7 spermatogonia per tubular cross-section could be observed.
Alkylating agents, hydroxyurea (HU), and certain non-malignant diseases can significantly deplete spermatogonial cell counts in young boys, according to research published in Human Reproduction.
Boys who received alkylating agents to treat cancer had significantly lower spermatogonial cell counts than control subjects or boys with malignant/nonmalignant diseases treated with non-alkylating agents.
Five of 6 SCD patients treated with HU had a totally depleted spermatogonial pool, and the remaining patient had a low spermatogonial cell count.
Five boys with non-malignant diseases who were not exposed to chemotherapy had significantly lower spermatogonial cell counts than controls.
“Our findings of a dramatic decrease in germ cell numbers in boys treated with alkylating agents and in sickle cell disease patients treated with hydroxyurea suggest that storing frozen testicular tissue from these boys should be performed before these treatments are initiated,” said study author Cecilia Petersen, MD, PhD, of Karolinska Institutet and University Hospital in Stockholm, Sweden.
“This needs to be communicated to physicians as well as patients and their parents or carers. However, until sperm that are able to fertilize eggs are produced from stored testicular tissue, we cannot confirm that germ cell quantity might determine the success of transplantation of the tissue in adulthood. Further research on this is needed to establish a realistic fertility preservation technique.”
Dr Petersen and her colleagues also noted that preserving testicular tissue may not be a viable option for boys who have low spermatogonial cell counts prior to treatment.
Patients and controls
For this study, the researchers analyzed testicular tissue from 32 boys facing treatments that carried a high risk of infertility—testicular irradiation, chemotherapy, or radiotherapy in advance of stem cell transplant.
Twenty boys had the tissue taken after initial chemotherapy, and 12 had it taken before starting any treatment.1
Eight patients had received chemotherapy with non-alkylating agents, 6 (all with malignancies) had received alkylating agents, and 6 (all with SCD) had received HU.
Diseases included acute lymphoblastic leukemia (n=6), SCD (n=6), acute myeloid leukemia (n=3), thalassemia major (n=3), neuroblastoma (n=2), juvenile myelomonocytic leukemia (n=2), myelodysplastic syndromes (n=2), primary immunodeficiency (n=2), Wilms tumor (n=1), adrenoleukodystrophy (n=1), hepatoblastoma (n=1), primitive neuroectodermal tumor (n=1), severe aplastic anemia (n=1), and Fanconi anemia (n=1).
The researchers compared samples from these 32 patients to 14 healthy testicular tissue samples stored in the biobank at the Karolinska University Hospital.
For both sample types, the team counted the number of spermatogonial cells found in a cross-section of seminiferous tubules.
“We could compare the number of spermatogonia with those found in the healthy boys as a way to estimate the effect of medical treatment or the disease itself on the future fertility of a patient,” explained study author Jan-Bernd Stukenborg, PhD, of Karolinska Institutet and University Hospital.
Impact of treatment
There was no significant difference in the mean quantity of spermatogonia per transverse tubular cross-section (S/T) between patients exposed to non-alkylating agents (1.7 ± 1.0, n=8) and biobank controls (4.1 ± 4.6, n=14).
However, samples from patients who received alkylating agents had a significantly lower mean S/T value (0.2 ± 0.3, n=6) than samples from patients treated with non-alkylating agents (P=0.003) and biobank controls (P<0.001).
“We found that the numbers of germ cells present in the cross-sections of the seminiferous tubules were significantly depleted and close to 0 in patients treated with alkylating agents,” Dr Stukenborg said.
Samples from the SCD patients also had a significantly lower mean S/T value (0.3 ± 0.6, n=6) than biobank controls (P=0.003).
Dr Stukenborg noted that the germ cell pool was totally depleted in 5 of the boys with SCD, and the pool was “very low” in the sixth SCD patient.
“This was not seen in patients who had not started treatment or were treated with non-alkylating agents or in the biobank tissues,” Dr Stukenborg said.2
He and his colleagues noted that it is possible for germ cells to recover to normal levels after treatment that is highly toxic to the testes, but high doses of alkylating agents and radiotherapy to the testicles are strongly associated with permanent or long-term infertility.
“The first group of boys who received bone marrow transplants are now reaching their thirties,” said study author Kirsi Jahnukainen, MD, PhD, of Helsinki University Central Hospital in Finland.
“Recent data suggest they may have a high chance of their sperm production recovering, even if they received high-dose alkylating therapies, so long as they had no testicular irradiation.”
Impact of disease
The researchers also found evidence to suggest that, for some boys, their disease may have affected spermatogonial cell counts before any treatment began.
Five patients with non-malignant disease who had not been exposed to chemotherapy (3 with thalassemia major, 1 with Fanconi anemia, and 1 with primary immunodeficiency) had a significantly lower mean S/T value (0.4 ± 0.5) than controls (P=0.006).
“Among patients who had not been treated previously with chemotherapy, there were several boys with a low number of germ cells for their age,” Dr Jahnukainen said.
“This suggests that some non-malignant diseases that require bone marrow transplants may affect the fertility of young boys even before exposure to therapy that is toxic for the testes.”
The researchers noted that a limitation of this study was that biobank samples had no detailed information regarding previous medical treatments and testicular volumes.
1. Testicular tissue is taken from patients under general anesthesia. The surgeon removes approximately 20% of the tissue from the testicular capsule in one of the testicles. For this study, a third of the tissue was taken to the Karolinska Institutet for analysis.
2. A recent meta-analysis showed that normal testicular tissue samples of newborns contain approximately 2.5 germ cells per tubular cross-section. This number decreases to approximately 1.2 within the first 3 years of age, followed by an increase up to 2.6 germ cells per tubular cross-section at 6 to 7 years, reaching a plateau until the age of 11. At the onset of puberty, an increase of up to 7 spermatogonia per tubular cross-section could be observed.
A new use for ibrutinib?
Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.
“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.
“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”
With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.
The researchers described this work in Leukemia.
“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”
“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”
This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.
“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.
The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.
“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.
Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.
“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.
“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”
Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.
“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.
“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”
With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.
The researchers described this work in Leukemia.
“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”
“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”
This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.
“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.
The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.
“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.
Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.
“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.
“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”
Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.
“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.
“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”
With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.
The researchers described this work in Leukemia.
“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”
“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”
This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.
“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.
The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.
“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.
Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.
“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.
“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”
FDA lifts hold on trial of MYC inhibitor
The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.
APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.
Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.
The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.
Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.
However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.
A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.
Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.
Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”
“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.
“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”
The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.
APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.
The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.
APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.
Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.
The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.
Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.
However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.
A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.
Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.
Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”
“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.
“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”
The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.
APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.
The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.
APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.
Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.
The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.
Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.
However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.
A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.
Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.
Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”
“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.
“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”
The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.
APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.
Art education benefits blood cancer patients
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
Drug shows promise for treating AML, MDS
Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.
The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.
ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.
These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.
ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.
In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.
The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.
The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.
“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.
The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.
“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”
Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.
The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.
“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”
ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.
In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.
Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.
The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.
ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.
These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.
ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.
In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.
The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.
The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.
“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.
The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.
“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”
Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.
The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.
“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”
ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.
In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.
Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.
The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.
ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.
These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.
ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.
In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.
The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.
The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.
“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.
The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.
“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”
Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.
The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.
“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”
ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.
In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.
Gene variants linked to survival after HSCT
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).
Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.
The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.
Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.
The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.
This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.
The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.
Variants in recipients
Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.
Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.
The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.
Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.
Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.
The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.
Donor variants linked to OS
Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.
The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.
And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.
There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).
And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.
Donor variants linked to TRM and DRM
Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.
There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).
Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).
The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.
“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
Agent exhibits activity in leukemias, MDS
The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.
The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).
When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.
Researchers said that, overall, the toxic effects of prexigebersen were manageable.
There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.
Still, the maximum tolerated dose of prexigebersen was not established.
These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.
Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.
In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.
There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.
All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.
For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).
In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).
Safety
Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.
One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.
There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.
The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).
In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.
There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.
Efficacy
According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.
Single-agent activity was observed in other patients as well.
Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.
Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy. Two of these patients had AML, and 1 had MDS.
Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.
Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.
Deaths
There were a total of 8 deaths.
One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.
Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.
The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.
The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).
When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.
Researchers said that, overall, the toxic effects of prexigebersen were manageable.
There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.
Still, the maximum tolerated dose of prexigebersen was not established.
These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.
Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.
In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.
There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.
All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.
For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).
In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).
Safety
Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.
One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.
There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.
The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).
In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.
There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.
Efficacy
According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.
Single-agent activity was observed in other patients as well.
Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.
Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy. Two of these patients had AML, and 1 had MDS.
Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.
Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.
Deaths
There were a total of 8 deaths.
One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.
Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.
The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.
The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).
When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.
Researchers said that, overall, the toxic effects of prexigebersen were manageable.
There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.
Still, the maximum tolerated dose of prexigebersen was not established.
These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.
Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.
In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.
There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.
All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.
For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).
In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).
Safety
Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.
One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.
There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.
The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).
In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.
There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.
Efficacy
According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.
Single-agent activity was observed in other patients as well.
Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.
Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy. Two of these patients had AML, and 1 had MDS.
Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.
Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.
Deaths
There were a total of 8 deaths.
One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.
Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.
Amgen withdraws application for darbepoetin alfa
Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.
Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.
Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.
At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.
This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).
The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.
In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.
Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.
In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.
Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.
Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.
Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.
At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.
This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).
The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.
In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.
Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.
In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.
Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.
Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.
Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.
At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.
This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).
The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.
In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.
Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.
In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.