Anemia

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The risk of developing myelodysplastic syndromes (MDS) or leukemias after treatment for early stage breast cancer is higher than previously reported, according to a study published in the Journal of Clinical Oncology.

Data from earlier studies showed that about 0.25% of breast cancer patients develop MDS or leukemia as a late effect of chemotherapy, said Judith Karp, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

But Dr Karp and her colleagues found the 10-year incidence of MDS and leukemia among breast cancer patients to be about 0.5%.

“[T]he cumulative risk over a decade is now shown to be twice as high as we thought it was, and that risk doesn’t seem to slow down 5 years after treatment,” Dr Karp said. “Most medical oncologists have come to think that the risk is early and short-lived. So this was a little bit of a wake-up call that we are not seeing any plateau of that risk, and it is higher.”

Dr Karp and her colleagues reviewed data on 20,063 breast cancer patients treated at 8 US cancer centers between 1998 and 2007 whose cancer recurrence and secondary cancer rates were recorded in a database kept by the National Comprehensive Cancer Network.

At a median follow-up of 5.1 years, 50 patients had developed a marrow neoplasm, including acute myeloid leukemia (n=24), MDS/acute myeloid leukemia (n=15), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=5), chronic myeloid leukemia (n=3), or acute lymphoblastic leukemia (n=3).

The risk of developing MDS/leukemia was about 7 times higher for patients who underwent surgery and received chemotherapy, compared to patients who did not receive chemotherapy. For patients who underwent surgery and received both chemotherapy and radiation, the risk was about 8 times higher.

The MDS/leukemia rates per 1000 person-years were 0.16 for surgery, 0.43 for surgery plus radiation, 0.46 for surgery plus chemotherapy, and 0.54 for all 3 modalities.

The cumulative incidence of MDS/leukemia doubled between years 5 and 10, rising from 0.24% to 0.48%. And only 9% of patients were alive at 10 years.

Antonio Wolff, MD, of the Johns Hopkins University School of Medicine, said this study could help early stage breast cancer patients and their physicians think more carefully about the use of preventive or adjuvant chemotherapy, especially when patients have a low risk of cancer recurrence.

“Our study provides useful information for physicians and patients to consider a potential downside of preventive or adjuvant chemotherapy in patients with very low risk of breast cancer recurrence,” he said.

“It could be a false and dangerous security blanket to some patients by exposing them to a small risk of serious late effects with little or no real benefit from the treatment.”

The researchers included a hypothetical case to put the risks of early stage breast cancer and its treatment in perspective. They described a 60-year-old woman in average health who was diagnosed with stage 1 breast cancer that was rapidly growing and estrogen receptor-positive.

The patient had an estimated 12.3% risk of dying of breast cancer after 10 years. She could improve her 10-year survival rate by 1.8% with 4 cycles of chemotherapy, but she would also increase her risk of MDS/leukemia over that same time by 0.5%.

Dr Wolff noted that it’s unclear whether the increased risk of MDS/leukemia after postsurgical chemotherapy applies to patients with other kinds of solid tumors, as the drug regimens used in breast cancer differ from those used for other cancers.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The risk of developing myelodysplastic syndromes (MDS) or leukemias after treatment for early stage breast cancer is higher than previously reported, according to a study published in the Journal of Clinical Oncology.

Data from earlier studies showed that about 0.25% of breast cancer patients develop MDS or leukemia as a late effect of chemotherapy, said Judith Karp, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

But Dr Karp and her colleagues found the 10-year incidence of MDS and leukemia among breast cancer patients to be about 0.5%.

“[T]he cumulative risk over a decade is now shown to be twice as high as we thought it was, and that risk doesn’t seem to slow down 5 years after treatment,” Dr Karp said. “Most medical oncologists have come to think that the risk is early and short-lived. So this was a little bit of a wake-up call that we are not seeing any plateau of that risk, and it is higher.”

Dr Karp and her colleagues reviewed data on 20,063 breast cancer patients treated at 8 US cancer centers between 1998 and 2007 whose cancer recurrence and secondary cancer rates were recorded in a database kept by the National Comprehensive Cancer Network.

At a median follow-up of 5.1 years, 50 patients had developed a marrow neoplasm, including acute myeloid leukemia (n=24), MDS/acute myeloid leukemia (n=15), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=5), chronic myeloid leukemia (n=3), or acute lymphoblastic leukemia (n=3).

The risk of developing MDS/leukemia was about 7 times higher for patients who underwent surgery and received chemotherapy, compared to patients who did not receive chemotherapy. For patients who underwent surgery and received both chemotherapy and radiation, the risk was about 8 times higher.

The MDS/leukemia rates per 1000 person-years were 0.16 for surgery, 0.43 for surgery plus radiation, 0.46 for surgery plus chemotherapy, and 0.54 for all 3 modalities.

The cumulative incidence of MDS/leukemia doubled between years 5 and 10, rising from 0.24% to 0.48%. And only 9% of patients were alive at 10 years.

Antonio Wolff, MD, of the Johns Hopkins University School of Medicine, said this study could help early stage breast cancer patients and their physicians think more carefully about the use of preventive or adjuvant chemotherapy, especially when patients have a low risk of cancer recurrence.

“Our study provides useful information for physicians and patients to consider a potential downside of preventive or adjuvant chemotherapy in patients with very low risk of breast cancer recurrence,” he said.

“It could be a false and dangerous security blanket to some patients by exposing them to a small risk of serious late effects with little or no real benefit from the treatment.”

The researchers included a hypothetical case to put the risks of early stage breast cancer and its treatment in perspective. They described a 60-year-old woman in average health who was diagnosed with stage 1 breast cancer that was rapidly growing and estrogen receptor-positive.

The patient had an estimated 12.3% risk of dying of breast cancer after 10 years. She could improve her 10-year survival rate by 1.8% with 4 cycles of chemotherapy, but she would also increase her risk of MDS/leukemia over that same time by 0.5%.

Dr Wolff noted that it’s unclear whether the increased risk of MDS/leukemia after postsurgical chemotherapy applies to patients with other kinds of solid tumors, as the drug regimens used in breast cancer differ from those used for other cancers.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The risk of developing myelodysplastic syndromes (MDS) or leukemias after treatment for early stage breast cancer is higher than previously reported, according to a study published in the Journal of Clinical Oncology.

Data from earlier studies showed that about 0.25% of breast cancer patients develop MDS or leukemia as a late effect of chemotherapy, said Judith Karp, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

But Dr Karp and her colleagues found the 10-year incidence of MDS and leukemia among breast cancer patients to be about 0.5%.

“[T]he cumulative risk over a decade is now shown to be twice as high as we thought it was, and that risk doesn’t seem to slow down 5 years after treatment,” Dr Karp said. “Most medical oncologists have come to think that the risk is early and short-lived. So this was a little bit of a wake-up call that we are not seeing any plateau of that risk, and it is higher.”

Dr Karp and her colleagues reviewed data on 20,063 breast cancer patients treated at 8 US cancer centers between 1998 and 2007 whose cancer recurrence and secondary cancer rates were recorded in a database kept by the National Comprehensive Cancer Network.

At a median follow-up of 5.1 years, 50 patients had developed a marrow neoplasm, including acute myeloid leukemia (n=24), MDS/acute myeloid leukemia (n=15), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=5), chronic myeloid leukemia (n=3), or acute lymphoblastic leukemia (n=3).

The risk of developing MDS/leukemia was about 7 times higher for patients who underwent surgery and received chemotherapy, compared to patients who did not receive chemotherapy. For patients who underwent surgery and received both chemotherapy and radiation, the risk was about 8 times higher.

The MDS/leukemia rates per 1000 person-years were 0.16 for surgery, 0.43 for surgery plus radiation, 0.46 for surgery plus chemotherapy, and 0.54 for all 3 modalities.

The cumulative incidence of MDS/leukemia doubled between years 5 and 10, rising from 0.24% to 0.48%. And only 9% of patients were alive at 10 years.

Antonio Wolff, MD, of the Johns Hopkins University School of Medicine, said this study could help early stage breast cancer patients and their physicians think more carefully about the use of preventive or adjuvant chemotherapy, especially when patients have a low risk of cancer recurrence.

“Our study provides useful information for physicians and patients to consider a potential downside of preventive or adjuvant chemotherapy in patients with very low risk of breast cancer recurrence,” he said.

“It could be a false and dangerous security blanket to some patients by exposing them to a small risk of serious late effects with little or no real benefit from the treatment.”

The researchers included a hypothetical case to put the risks of early stage breast cancer and its treatment in perspective. They described a 60-year-old woman in average health who was diagnosed with stage 1 breast cancer that was rapidly growing and estrogen receptor-positive.

The patient had an estimated 12.3% risk of dying of breast cancer after 10 years. She could improve her 10-year survival rate by 1.8% with 4 cycles of chemotherapy, but she would also increase her risk of MDS/leukemia over that same time by 0.5%.

Dr Wolff noted that it’s unclear whether the increased risk of MDS/leukemia after postsurgical chemotherapy applies to patients with other kinds of solid tumors, as the drug regimens used in breast cancer differ from those used for other cancers.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Doctor examines child with

sickle cell disease

Credit: St. Jude Hospital

SAN FRANCISCO—Magnesium does not improve outcomes in children hospitalized for sickle cell pain crises, results of the MAGiC study suggest.

Researchers hypothesized that magnesium—a known vasodilator, anti-inflammatory, and pain reliever—could alter the pathophysiology of pain crises.

However, when compared to normal saline, intravenous (IV) magnesium did not shorten hospital stays, lessen opioid use, or improve patients’ quality of life.

David C. Brousseau, MD, of the Medical College of Wisconsin and the Children’s Hospital of Wisconsin in Milwaukee, presented the results of this study at the 2014 ASH Annual Meeting (abstract 88).

Dr Brousseau noted that vasoocclusive crises are the most common acute complication of sickle cell disease and the most frequent cause of acute care or emergency department visits and hospitalizations. But recent changes in treatment have been minimal, with the judicious use of IV fluid and IV opioids being the mainstays of therapy.

“There have been few multicenter clinical trials evaluating new treatments, in part, due to a long history of difficulty with enrollment in interventional trials for sickle cell crises,” he continued. “These enrollment difficulties have been due to an inability to consent or to consent in a timely manner, leading to delayed initiation of study drug.”

With the MAGiC trial, Dr Brousseau and his colleagues sought to overcome this problem through a collaboration between pediatric emergency medicine physicians and pediatric hematologists.

In this randomized, double-blind trial, the researchers compared IV magnesium to normal saline. They enrolled children ages 4 to 21, with hemoglobin SS or hemoglobin SB° thalassemia, who were hospitalized after failing emergency department management for pain.

A total of 208 children were enrolled at 8 study sites over 3 years. Four children were excluded before receiving treatment, so 101 were randomized to receive magnesium and 103 to saline.

The children received 40 mg/kg of IV magnesium every 8 hours for a total of 6 doses or normal saline of an equivalent volume (1 mL/kg).

The treatment groups were well-balanced, with similar baseline age, sex, genotype, weight, history of acute chest syndrome or asthma, previous hospitalizations within the past 3 years, use of hydroxyurea, and days of pain prior to arrival.

The median time from the first emergency department opioid to the first study drug infusion was 7.3 hours in the magnesium group and 7.5 hours in the saline group.

For the study’s primary outcome, the researchers assessed patients’ length of stay from the first study drug infusion until 12 hours after the last IV opioid dose or the time of discharge, whichever came first.

“Approximately 50% of children [overall] met the study endpoint within 52 hours, and 25% met the study endpoint within 24 hours of the first drug infusion,” Dr Brousseau noted.

And there was no significant difference in the median length of stay between the treatment arms—56 hours in the magnesium arm and 47 hours in the placebo arm (P=0.264).

A secondary outcome was opioid use, recorded as morphine equivalents. There was no significant difference with this outcome, either. Patients in the magnesium arm received 1.46 mg/kg of morphine equivalents, compared to 1.28 mg/kg in the saline arm (P=0.12).

The researchers also assessed quality of life using the PedsQL sickle cell disease-specific module, fatigue module, and generic module. At 48 hours after the first infusion, there was no significant difference in quality of life scores between the treatment groups for any of the modules (P=0.17, 0.26, and 0.94, respectively). The same was true 1 week after discharge (P=0.55, 0.82, and 0.36, respectively).

As for safety, there was no significant difference between the treatment arms for most measures. However, patients in the magnesium arm were more likely to experience warmth upon infusion, at 26%, compared to 2% in the saline arm (P<0.01).

Acute chest syndrome occurred in 16% of patients in the magnesium arm and 14% in the saline arm (P=0.78). Hypotension occurred in 4% and 1%, respectively (P=0.39). And rehospitalization within 7 days occurred in 12% and 7%, respectively (P=0.11).

In closing, Dr Brousseau noted that, although the researchers did not prove their hypothesis correct, the MAGiC study was a success in one respect.

“Intravenous magnesium does not shorten length of stay, lessen opioid use, or improve quality of life in children hospitalized for sickle cell pain crises,” he said. “[However,] a collaboration between pediatric emergency department medicine physicians and pediatric hematologists allowed for successful enrollment in an acute intervention trial with a median time to first study drug of 7.5 hours.”

Stairs in the Moscone Center,

site of the ASH Annual Meeting

Photo courtesy of ASH

SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.

Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.

Investigators reported the trial results at the 2014 ASH Annual Meeting.

Luspatercept in β-thalassemia

Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.

The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.

Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.

And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.

The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.

Luspatercept efficacy

Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.

They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”

And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.

Luspatercept safety

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.

Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.

With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”

Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.

Sotatercept in MDS and CMML with anemia

Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.

Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.

They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).

Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.

Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.

Patients were a median age of 71, and 70% were male.

They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.

Sotatercept efficacy

The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.

Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.

Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.

Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.

Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.

Sotatercept safety

“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”

Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).

Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.

Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”

He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.

He presented the data as abstract 3251. The study was supported by Celgene Corporation.

*One patient was excluded from the efficacy analysis due to a protocol violation.

Stairs in the Moscone Center,

site of the ASH Annual Meeting

Photo courtesy of ASH

SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.

Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.

Investigators reported the trial results at the 2014 ASH Annual Meeting.

Luspatercept in β-thalassemia

Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.

The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.

Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.

And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.

The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.

Luspatercept efficacy

Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.

They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”

And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.

Luspatercept safety

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.

Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.

With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”

Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.

Sotatercept in MDS and CMML with anemia

Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.

Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.

They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).

Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.

Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.

Patients were a median age of 71, and 70% were male.

They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.

Sotatercept efficacy

The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.

Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.

Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.

Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.

Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.

Sotatercept safety

“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”

Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).

Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.

Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”

He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.

He presented the data as abstract 3251. The study was supported by Celgene Corporation.

*One patient was excluded from the efficacy analysis due to a protocol violation.

Stairs in the Moscone Center,

site of the ASH Annual Meeting

Photo courtesy of ASH

SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.

Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.

Investigators reported the trial results at the 2014 ASH Annual Meeting.

Luspatercept in β-thalassemia

Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.

The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.

Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.

And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.

The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.

Luspatercept efficacy

Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.

They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”

And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.

Luspatercept safety

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.

Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.

With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”

Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.

Sotatercept in MDS and CMML with anemia

Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.

Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.

They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).

Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.

Their white blood cell counts had to be under 13,000/μL, and they had to have no response, loss of response, or low chance of response to ESAs, reflected by serum erythropoietin of more than 500 mIU/mL.

Patients were a median age of 71, and 70% were male.

They received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks for up to 24 months following the first treatment.

Sotatercept efficacy

The investigators evaluated efficacy for the entire cohort as well as in subgroups of patients with high transfusion burden (HTB) and low transfusion burden (LTB). Patients were defined as HTB if they required RBC transfusions of 4 or more units every 8 weeks and LTB as less than 4 units per 8 weeks.

Overall, 45% (24/53) of the evaluable patients achieved hematologic improvement as defined by IWG 2006 criteria.

Forty-two percent of HTB patients had a reduction in their transfusion burden of 4 or more RBC units per 8 weeks, with a median duration of longest response of 106 days (range, 62 to 345+). Eleven percent (5/44) achieved RBC transfusion independence of 56 days or more.

Sixty-three percent (5/8) of LTB patients achieved both RBC transfusion independence of 56 days or more and a mean hemoglobin increase of 1.5 mg/dL or more for at least 8 weeks.

Their maximum mean hemoglobin increase ranged from 1.9 to 4.4 g/dL, and the mean duration of RBC transfusion independence ranged from 76 to 233+ days. Of these 8 patients, 67% were in the 1.0 mg/kg cohort.

Sotatercept safety

“Most of the adverse events were not necessarily related to the treatment,” Dr Komrokji said, “and they were grade 1 or grade 2 toxicity.”

Twenty of 54* patients (37%) experienced 1 or more treatment-related adverse events, the most common of which were fatigue/asthenia (13%), headache (9%), decreased appetite (7%), nausea (7%), and dyspnea (6%).

Three patients discontinued the study due to treatment-emergent adverse events that were possibly related to sotatercept. One was for grade 2 hemolytic anemia, 1 for grade 3 hypertension, and 1 for grade 2 muscle weakness.

Dr Komrokji concluded saying the results showed “promising evidence of clinical activity” in these ESA-refractory, anemic, lower-risk MDS and CMML patients who have a “challenging and unmet need for treatment.”

He indicated that further exploration of sotatercept at higher dose levels and for longer treatment periods is planned and ongoing.

He presented the data as abstract 3251. The study was supported by Celgene Corporation.

*One patient was excluded from the efficacy analysis due to a protocol violation.

Doctor consults with a family

Credit: Rhoda Baer

The American Society of Hematology (ASH) has released a second list of 5 commonly used tests, treatments, and procedures that physicians and patients should question in certain circumstances.

The additional items join an initial list of practices released last year as part of the Choosing Wisely^® campaign, an initiative of the ABIM Foundation that aims to prompt conversations between patients and physicians about the necessity and potential harm of certain procedures.

These new “practices to question” are also highlighted in a manuscript published in Blood, which further describes the methods for developing the list and the evidentiary basis of the recommendations.

The new recommendations include:

1. Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor.
2. Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.
3. Don’t perform baseline or routine surveillance CT scans in patients with asymptomatic, early stage chronic lymphocytic leukemia.
4. Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT.
5. Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.

The second Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations.

“Unnecessary treatments or tests not only add waste to the healthcare system, but, in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St Michael’s Hospital and the University of Toronto and chair of the ASH Choosing Wisely Task Force.

“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research.”

The dominant guiding principle for ASH’s list is the concept of avoiding harm. The four other established guiding principles of ASH’s involvement in the Choosing Wisely campaign are strength of evidence, aggregate cost, frequency, and making recommendations within the purview of hematology. This year, the task force added a sixth overarching principle of potential impact in the field.

“Choosing Wisely set out to stimulate conversations about waste and overuse in our healthcare system,” said Richard J. Baron, MD, President and CEO of the ABIM Foundation.

“We’ve been fortunate to be joined in this effort by many dedicated partners—including ASH—who have committed to addressing unnecessary care in their specialty. ASH’s second Choosing Wisely list gives clinicians and patients a new and important tool to help inform their conversations about what care is best for the patient.”

Doctor consults with a family

Credit: Rhoda Baer

The American Society of Hematology (ASH) has released a second list of 5 commonly used tests, treatments, and procedures that physicians and patients should question in certain circumstances.

The additional items join an initial list of practices released last year as part of the Choosing Wisely^® campaign, an initiative of the ABIM Foundation that aims to prompt conversations between patients and physicians about the necessity and potential harm of certain procedures.

These new “practices to question” are also highlighted in a manuscript published in Blood, which further describes the methods for developing the list and the evidentiary basis of the recommendations.

The new recommendations include:

1. Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor.
2. Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.
3. Don’t perform baseline or routine surveillance CT scans in patients with asymptomatic, early stage chronic lymphocytic leukemia.
4. Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT.
5. Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.

The second Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations.

“Unnecessary treatments or tests not only add waste to the healthcare system, but, in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St Michael’s Hospital and the University of Toronto and chair of the ASH Choosing Wisely Task Force.

“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research.”

The dominant guiding principle for ASH’s list is the concept of avoiding harm. The four other established guiding principles of ASH’s involvement in the Choosing Wisely campaign are strength of evidence, aggregate cost, frequency, and making recommendations within the purview of hematology. This year, the task force added a sixth overarching principle of potential impact in the field.

“Choosing Wisely set out to stimulate conversations about waste and overuse in our healthcare system,” said Richard J. Baron, MD, President and CEO of the ABIM Foundation.

“We’ve been fortunate to be joined in this effort by many dedicated partners—including ASH—who have committed to addressing unnecessary care in their specialty. ASH’s second Choosing Wisely list gives clinicians and patients a new and important tool to help inform their conversations about what care is best for the patient.”

Doctor consults with a family

Credit: Rhoda Baer

The American Society of Hematology (ASH) has released a second list of 5 commonly used tests, treatments, and procedures that physicians and patients should question in certain circumstances.

The additional items join an initial list of practices released last year as part of the Choosing Wisely^® campaign, an initiative of the ABIM Foundation that aims to prompt conversations between patients and physicians about the necessity and potential harm of certain procedures.

These new “practices to question” are also highlighted in a manuscript published in Blood, which further describes the methods for developing the list and the evidentiary basis of the recommendations.

The new recommendations include:

1. Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor.
2. Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.
3. Don’t perform baseline or routine surveillance CT scans in patients with asymptomatic, early stage chronic lymphocytic leukemia.
4. Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT.
5. Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.

The second Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations.

“Unnecessary treatments or tests not only add waste to the healthcare system, but, in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St Michael’s Hospital and the University of Toronto and chair of the ASH Choosing Wisely Task Force.

“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research.”

The dominant guiding principle for ASH’s list is the concept of avoiding harm. The four other established guiding principles of ASH’s involvement in the Choosing Wisely campaign are strength of evidence, aggregate cost, frequency, and making recommendations within the purview of hematology. This year, the task force added a sixth overarching principle of potential impact in the field.

“Choosing Wisely set out to stimulate conversations about waste and overuse in our healthcare system,” said Richard J. Baron, MD, President and CEO of the ABIM Foundation.

“We’ve been fortunate to be joined in this effort by many dedicated partners—including ASH—who have committed to addressing unnecessary care in their specialty. ASH’s second Choosing Wisely list gives clinicians and patients a new and important tool to help inform their conversations about what care is best for the patient.”

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

A sickled red blood cell

and a normal one

Credit: Betty Pace

Aggressive public health campaigns are needed to educate people in sub-Saharan Africa about sickle cell disease (SCD), according to a professor of health studies.

William Ebomoyi, PhD, of Chicago State University in Illinois, investigated the prevalence of SCD in sub-Saharan Africa, assessed the physical and emotional ramifications of the disease, evaluated ethical and legal issues related to SCD, and assessed the socio-cultural implications of the disease.

He reported his findings in the International Journal of Medical Engineering and Informatics.

Dr Ebomoyi explained that SCD occurs from a change in valine to glutamine substitution in the sixth amino acid position of the beta globin chain. If one of the two beta globin genes is affected, a person simply has sickle cell trait (SCT), but if both genes are involved, the person has SCD.

If two people with SCT decide to have a child, there is a 50% chance that child will have SCT, a 25% chance the child will have SCD, and a 25% chance the child will have neither condition. If one parent has SCT, there is a 50% chance the child will have SCT.

In some communities in sub-Saharan Africa, up to 2% of all children are born with SCD. And the prevalence of SCT ranges from 10% to 40% across equatorial Africa.

Dr Ebomoyi said early screening to identify infants with SCD is needed, as life-threatening complications can occur within the first 3 years of life. Unfortunately, the method of choice for SCD screening—cellulose acetate accompanied by citrate agar electrophoresis—is only available in two sub-Saharan African nations—South Africa and Ghana.

Similarly, innovative SCD treatment techniques have not been introduced in sub-Saharan African nations. There are not enough well-trained physicians, Dr Ebomoyi said. In fact, many SCD patients are treated improperly by traditional African healers.

Furthermore, aside from Senegal and Liberia, sub-Saharan African nations spend less than 10% of their gross domestic product on healthcare. And inadequate funding plays a major role in the high prevalence of SCD in these nations.

For all these reasons, it is important to raise awareness in sub-Saharan Africa about SCD, according to Dr Ebomoyi. He said members of the public should be aware of how they can pass SCD down to their children and inform their partners if they have SCT prior to conceiving a child.

He added that sickle cell education programs should be integrated into the curriculum of elementary, secondary, and tertiary academic institutions.

The abstract of this article, “Ethical, legal, social, and financial implications of neonatal screening for sickle cell anaemia in Sub-Sahara Africa in the age of genomic science,” can be found on the Inderscience Publishers website.

A sickled red blood cell

and a normal one

Credit: Betty Pace

Aggressive public health campaigns are needed to educate people in sub-Saharan Africa about sickle cell disease (SCD), according to a professor of health studies.

William Ebomoyi, PhD, of Chicago State University in Illinois, investigated the prevalence of SCD in sub-Saharan Africa, assessed the physical and emotional ramifications of the disease, evaluated ethical and legal issues related to SCD, and assessed the socio-cultural implications of the disease.

He reported his findings in the International Journal of Medical Engineering and Informatics.

Dr Ebomoyi explained that SCD occurs from a change in valine to glutamine substitution in the sixth amino acid position of the beta globin chain. If one of the two beta globin genes is affected, a person simply has sickle cell trait (SCT), but if both genes are involved, the person has SCD.

If two people with SCT decide to have a child, there is a 50% chance that child will have SCT, a 25% chance the child will have SCD, and a 25% chance the child will have neither condition. If one parent has SCT, there is a 50% chance the child will have SCT.

In some communities in sub-Saharan Africa, up to 2% of all children are born with SCD. And the prevalence of SCT ranges from 10% to 40% across equatorial Africa.

Dr Ebomoyi said early screening to identify infants with SCD is needed, as life-threatening complications can occur within the first 3 years of life. Unfortunately, the method of choice for SCD screening—cellulose acetate accompanied by citrate agar electrophoresis—is only available in two sub-Saharan African nations—South Africa and Ghana.

Similarly, innovative SCD treatment techniques have not been introduced in sub-Saharan African nations. There are not enough well-trained physicians, Dr Ebomoyi said. In fact, many SCD patients are treated improperly by traditional African healers.

Furthermore, aside from Senegal and Liberia, sub-Saharan African nations spend less than 10% of their gross domestic product on healthcare. And inadequate funding plays a major role in the high prevalence of SCD in these nations.

For all these reasons, it is important to raise awareness in sub-Saharan Africa about SCD, according to Dr Ebomoyi. He said members of the public should be aware of how they can pass SCD down to their children and inform their partners if they have SCT prior to conceiving a child.

He added that sickle cell education programs should be integrated into the curriculum of elementary, secondary, and tertiary academic institutions.

The abstract of this article, “Ethical, legal, social, and financial implications of neonatal screening for sickle cell anaemia in Sub-Sahara Africa in the age of genomic science,” can be found on the Inderscience Publishers website.

A sickled red blood cell

and a normal one

Credit: Betty Pace

Aggressive public health campaigns are needed to educate people in sub-Saharan Africa about sickle cell disease (SCD), according to a professor of health studies.

William Ebomoyi, PhD, of Chicago State University in Illinois, investigated the prevalence of SCD in sub-Saharan Africa, assessed the physical and emotional ramifications of the disease, evaluated ethical and legal issues related to SCD, and assessed the socio-cultural implications of the disease.

He reported his findings in the International Journal of Medical Engineering and Informatics.

Dr Ebomoyi explained that SCD occurs from a change in valine to glutamine substitution in the sixth amino acid position of the beta globin chain. If one of the two beta globin genes is affected, a person simply has sickle cell trait (SCT), but if both genes are involved, the person has SCD.

If two people with SCT decide to have a child, there is a 50% chance that child will have SCT, a 25% chance the child will have SCD, and a 25% chance the child will have neither condition. If one parent has SCT, there is a 50% chance the child will have SCT.

In some communities in sub-Saharan Africa, up to 2% of all children are born with SCD. And the prevalence of SCT ranges from 10% to 40% across equatorial Africa.

Dr Ebomoyi said early screening to identify infants with SCD is needed, as life-threatening complications can occur within the first 3 years of life. Unfortunately, the method of choice for SCD screening—cellulose acetate accompanied by citrate agar electrophoresis—is only available in two sub-Saharan African nations—South Africa and Ghana.

Similarly, innovative SCD treatment techniques have not been introduced in sub-Saharan African nations. There are not enough well-trained physicians, Dr Ebomoyi said. In fact, many SCD patients are treated improperly by traditional African healers.

Furthermore, aside from Senegal and Liberia, sub-Saharan African nations spend less than 10% of their gross domestic product on healthcare. And inadequate funding plays a major role in the high prevalence of SCD in these nations.

For all these reasons, it is important to raise awareness in sub-Saharan Africa about SCD, according to Dr Ebomoyi. He said members of the public should be aware of how they can pass SCD down to their children and inform their partners if they have SCT prior to conceiving a child.

He added that sickle cell education programs should be integrated into the curriculum of elementary, secondary, and tertiary academic institutions.

The abstract of this article, “Ethical, legal, social, and financial implications of neonatal screening for sickle cell anaemia in Sub-Sahara Africa in the age of genomic science,” can be found on the Inderscience Publishers website.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted orphan drug designation for CCX168, an oral inhibitor targeting the receptor for the complement protein C5a, to treat atypical hemolytic uremic syndrome (aHUS).

This rare but life-threatening disease causes inflammation of the blood vessels and thrombus formation throughout the body.

Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs. Roughly 10% to 15% of patients die in the initial, acute phase of aHUS.

The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.

“Given the life-threatening nature of aHUS, we are very pleased with the granting of orphan drug designation for CCX168 in this disease,” said Thomas J. Schall, PhD, president and chief executive officer of ChemoCentryx, Inc., the company developing CCX168.

ChemoCentryx has generated positive preclinical data that suggest an important role of C5a receptor inhibition in reducing microvasculature thrombosis formation in aHUS.

The company plans to initiate a phase 2 proof-of-concept study in patients with aHUS by the end of 2014.

CCX168 is also in phase 2 development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The orphan designation for CCX168 will provide ChemoCentryx with a 7-year period of US marketing exclusivity if the drug is approved to treat aHUS, tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance, and the waiver of prescription drug user fees.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted orphan drug designation for CCX168, an oral inhibitor targeting the receptor for the complement protein C5a, to treat atypical hemolytic uremic syndrome (aHUS).

This rare but life-threatening disease causes inflammation of the blood vessels and thrombus formation throughout the body.

Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs. Roughly 10% to 15% of patients die in the initial, acute phase of aHUS.

The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.

“Given the life-threatening nature of aHUS, we are very pleased with the granting of orphan drug designation for CCX168 in this disease,” said Thomas J. Schall, PhD, president and chief executive officer of ChemoCentryx, Inc., the company developing CCX168.

ChemoCentryx has generated positive preclinical data that suggest an important role of C5a receptor inhibition in reducing microvasculature thrombosis formation in aHUS.

The company plans to initiate a phase 2 proof-of-concept study in patients with aHUS by the end of 2014.

CCX168 is also in phase 2 development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The orphan designation for CCX168 will provide ChemoCentryx with a 7-year period of US marketing exclusivity if the drug is approved to treat aHUS, tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance, and the waiver of prescription drug user fees.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted orphan drug designation for CCX168, an oral inhibitor targeting the receptor for the complement protein C5a, to treat atypical hemolytic uremic syndrome (aHUS).

This rare but life-threatening disease causes inflammation of the blood vessels and thrombus formation throughout the body.

Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs. Roughly 10% to 15% of patients die in the initial, acute phase of aHUS.

The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.

“Given the life-threatening nature of aHUS, we are very pleased with the granting of orphan drug designation for CCX168 in this disease,” said Thomas J. Schall, PhD, president and chief executive officer of ChemoCentryx, Inc., the company developing CCX168.

ChemoCentryx has generated positive preclinical data that suggest an important role of C5a receptor inhibition in reducing microvasculature thrombosis formation in aHUS.

The company plans to initiate a phase 2 proof-of-concept study in patients with aHUS by the end of 2014.

CCX168 is also in phase 2 development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The orphan designation for CCX168 will provide ChemoCentryx with a 7-year period of US marketing exclusivity if the drug is approved to treat aHUS, tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance, and the waiver of prescription drug user fees.

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]