Anemia

Two distinct proteins appear to control the switch from fetal to adult globin, based on studies performed in a humanized mouse model and human cells. The findings suggest therapies that target both proteins might induce a fetal-type globin state, which could prove therapeutically useful in individuals with human hemoglobinopathies such as sickle cell disease and thalassemia.

The leukemia/lymphoma-related factor (LRF) and B-cell lymphoma/leukemia 11A (BCL11A) are independently involved in the switch, and blocking their production may turn on fetal globin expression, Takeshi Masuda, Ph.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues report (SCIENCE. 2015 Jan 15;351[6270]:285-9)

Using a humanized mouse model, the researchers knocked out the ZBTB7A gene, which is responsible for producing LRF. This action boosted the expression of genes that control fetal but not adult-type hemoglobin. Knocking out the gene in human cells also resulted in an increase in fetal hemoglobin proteins.

The researchers then examined BCL11A, which is involved with fetal hemoglobin but does not suppress it. When genes were knocked out for both ZBTB7A and BCL11A in the mice, fetal hemoglobin represented a 91%-94% greater percentage of total hemoglobin than when either gene alone was knocked out.

The research was supported by awards and/or grants from the National Institute of Diabetes and Digestive and Kidney Disease, the Doris Duke Charitable Foundation, the National Institutes of Health, and the American Society of Hematology. Dr. Masuda, along with two other study authors, is a contributor to a patent application filed on behalf of Brigham and Women’s Hospital related to therapeutic targeting of the pathways.

Click here to read the study at Science.

[email protected]

Two distinct proteins appear to control the switch from fetal to adult globin, based on studies performed in a humanized mouse model and human cells. The findings suggest therapies that target both proteins might induce a fetal-type globin state, which could prove therapeutically useful in individuals with human hemoglobinopathies such as sickle cell disease and thalassemia.

The leukemia/lymphoma-related factor (LRF) and B-cell lymphoma/leukemia 11A (BCL11A) are independently involved in the switch, and blocking their production may turn on fetal globin expression, Takeshi Masuda, Ph.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues report (SCIENCE. 2015 Jan 15;351[6270]:285-9)

Using a humanized mouse model, the researchers knocked out the ZBTB7A gene, which is responsible for producing LRF. This action boosted the expression of genes that control fetal but not adult-type hemoglobin. Knocking out the gene in human cells also resulted in an increase in fetal hemoglobin proteins.

The researchers then examined BCL11A, which is involved with fetal hemoglobin but does not suppress it. When genes were knocked out for both ZBTB7A and BCL11A in the mice, fetal hemoglobin represented a 91%-94% greater percentage of total hemoglobin than when either gene alone was knocked out.

The research was supported by awards and/or grants from the National Institute of Diabetes and Digestive and Kidney Disease, the Doris Duke Charitable Foundation, the National Institutes of Health, and the American Society of Hematology. Dr. Masuda, along with two other study authors, is a contributor to a patent application filed on behalf of Brigham and Women’s Hospital related to therapeutic targeting of the pathways.

Click here to read the study at Science.

[email protected]

Two distinct proteins appear to control the switch from fetal to adult globin, based on studies performed in a humanized mouse model and human cells. The findings suggest therapies that target both proteins might induce a fetal-type globin state, which could prove therapeutically useful in individuals with human hemoglobinopathies such as sickle cell disease and thalassemia.

The leukemia/lymphoma-related factor (LRF) and B-cell lymphoma/leukemia 11A (BCL11A) are independently involved in the switch, and blocking their production may turn on fetal globin expression, Takeshi Masuda, Ph.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues report (SCIENCE. 2015 Jan 15;351[6270]:285-9)

Using a humanized mouse model, the researchers knocked out the ZBTB7A gene, which is responsible for producing LRF. This action boosted the expression of genes that control fetal but not adult-type hemoglobin. Knocking out the gene in human cells also resulted in an increase in fetal hemoglobin proteins.

The researchers then examined BCL11A, which is involved with fetal hemoglobin but does not suppress it. When genes were knocked out for both ZBTB7A and BCL11A in the mice, fetal hemoglobin represented a 91%-94% greater percentage of total hemoglobin than when either gene alone was knocked out.

The research was supported by awards and/or grants from the National Institute of Diabetes and Digestive and Kidney Disease, the Doris Duke Charitable Foundation, the National Institutes of Health, and the American Society of Hematology. Dr. Masuda, along with two other study authors, is a contributor to a patent application filed on behalf of Brigham and Women’s Hospital related to therapeutic targeting of the pathways.

Click here to read the study at Science.

[email protected]

Lab mouse

The protein kinase CHK1 may be a therapeutic target for Fanconi anemia (FA), according to researchers.

They studied induced pluripotent stem cells (iPSCs) derived from FA patients and found the FA DNA repair pathway was essential for the cells’ proliferation and survival.

The team also discovered that CHK1 played a “crucial” role in iPSCs’ sensitivity to accrued DNA damage, and inhibiting CHK1 allowed FA-deficient iPSCs to grow

normally.

The team relayed these findings in Stem Cell Reports.

“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options,” said study author Susanne Wells, PhD, of the Cincinnati Children’s Hospital Medical Center in Ohio.

“Our findings also raise a number of important questions, so there is a lot more to be done.”

For this study, Dr Wells and her colleagues used iPSCs reprogrammed from mature skin and connective tissue cells donated by FA patients. The cells had a defective FA DNA repair pathway.

The researchers studied the iPSCs in culture and injected them into humanized mouse models, monitoring their genetic, molecular, and developmental progression.

Even with defective FA DNA repair, the iPSCs retained their ability to transform into different tissues, and humanized mice injected with the defective cells started to form teratomas.

However, the DNA repair defect started to kill off the iPSCs by blocking cell division and causing apoptosis.

The researchers noticed that CHK1, which serves as a DNA regulatory checkpoint during cell division, was hyperactive in the iPSCs, which hastened their death.

So the team used pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle. This allowed them to override what are usually unfixable errors in the FA repair pathway.

After targeted treatment, FA-pathway-deficient iPSCs resumed dividing and expanding normally.

The researchers said that, to their surprise, the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities. Because of this, they speculate that a compensating DNA repair process is engaged in the reinvigorated cells.

Because this unidentified repair process may also rescue the DNA repair defect in the different tissue types affected by FA, Dr Wells and her colleagues believe their study may point to an approach that treats all clinical manifestations of the disease, including anemia and cancer.

“A key question for us is, ‘What type of DNA repair kicks in under these conditions, and is it error-free or error-prone?’” Dr Wells explained. “A novel mode of emergency DNA repair might indeed be discovered in the [iPSCs]. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”

The researchers plan to follow up this study with additional testing in humanized and genetic mouse models. They said they will attempt to improve embryonic development and post-birth fitness in FA-pathway-deficient mice with timed application of a CHK1 inhibitor.

The team will monitor the mice as they age and use genetic sequencing to screen for disease-causing mutations. And they will look for evidence of a DNA repair process (either novel or existing) in the FA-deficient mice.

Lab mouse

The protein kinase CHK1 may be a therapeutic target for Fanconi anemia (FA), according to researchers.

They studied induced pluripotent stem cells (iPSCs) derived from FA patients and found the FA DNA repair pathway was essential for the cells’ proliferation and survival.

The team also discovered that CHK1 played a “crucial” role in iPSCs’ sensitivity to accrued DNA damage, and inhibiting CHK1 allowed FA-deficient iPSCs to grow

normally.

The team relayed these findings in Stem Cell Reports.

“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options,” said study author Susanne Wells, PhD, of the Cincinnati Children’s Hospital Medical Center in Ohio.

“Our findings also raise a number of important questions, so there is a lot more to be done.”

For this study, Dr Wells and her colleagues used iPSCs reprogrammed from mature skin and connective tissue cells donated by FA patients. The cells had a defective FA DNA repair pathway.

The researchers studied the iPSCs in culture and injected them into humanized mouse models, monitoring their genetic, molecular, and developmental progression.

Even with defective FA DNA repair, the iPSCs retained their ability to transform into different tissues, and humanized mice injected with the defective cells started to form teratomas.

However, the DNA repair defect started to kill off the iPSCs by blocking cell division and causing apoptosis.

The researchers noticed that CHK1, which serves as a DNA regulatory checkpoint during cell division, was hyperactive in the iPSCs, which hastened their death.

So the team used pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle. This allowed them to override what are usually unfixable errors in the FA repair pathway.

After targeted treatment, FA-pathway-deficient iPSCs resumed dividing and expanding normally.

The researchers said that, to their surprise, the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities. Because of this, they speculate that a compensating DNA repair process is engaged in the reinvigorated cells.

Because this unidentified repair process may also rescue the DNA repair defect in the different tissue types affected by FA, Dr Wells and her colleagues believe their study may point to an approach that treats all clinical manifestations of the disease, including anemia and cancer.

“A key question for us is, ‘What type of DNA repair kicks in under these conditions, and is it error-free or error-prone?’” Dr Wells explained. “A novel mode of emergency DNA repair might indeed be discovered in the [iPSCs]. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”

The researchers plan to follow up this study with additional testing in humanized and genetic mouse models. They said they will attempt to improve embryonic development and post-birth fitness in FA-pathway-deficient mice with timed application of a CHK1 inhibitor.

The team will monitor the mice as they age and use genetic sequencing to screen for disease-causing mutations. And they will look for evidence of a DNA repair process (either novel or existing) in the FA-deficient mice.

Lab mouse

The protein kinase CHK1 may be a therapeutic target for Fanconi anemia (FA), according to researchers.

They studied induced pluripotent stem cells (iPSCs) derived from FA patients and found the FA DNA repair pathway was essential for the cells’ proliferation and survival.

The team also discovered that CHK1 played a “crucial” role in iPSCs’ sensitivity to accrued DNA damage, and inhibiting CHK1 allowed FA-deficient iPSCs to grow

normally.

The team relayed these findings in Stem Cell Reports.

“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options,” said study author Susanne Wells, PhD, of the Cincinnati Children’s Hospital Medical Center in Ohio.

“Our findings also raise a number of important questions, so there is a lot more to be done.”

For this study, Dr Wells and her colleagues used iPSCs reprogrammed from mature skin and connective tissue cells donated by FA patients. The cells had a defective FA DNA repair pathway.

The researchers studied the iPSCs in culture and injected them into humanized mouse models, monitoring their genetic, molecular, and developmental progression.

Even with defective FA DNA repair, the iPSCs retained their ability to transform into different tissues, and humanized mice injected with the defective cells started to form teratomas.

However, the DNA repair defect started to kill off the iPSCs by blocking cell division and causing apoptosis.

The researchers noticed that CHK1, which serves as a DNA regulatory checkpoint during cell division, was hyperactive in the iPSCs, which hastened their death.

So the team used pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle. This allowed them to override what are usually unfixable errors in the FA repair pathway.

After targeted treatment, FA-pathway-deficient iPSCs resumed dividing and expanding normally.

The researchers said that, to their surprise, the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities. Because of this, they speculate that a compensating DNA repair process is engaged in the reinvigorated cells.

Because this unidentified repair process may also rescue the DNA repair defect in the different tissue types affected by FA, Dr Wells and her colleagues believe their study may point to an approach that treats all clinical manifestations of the disease, including anemia and cancer.

“A key question for us is, ‘What type of DNA repair kicks in under these conditions, and is it error-free or error-prone?’” Dr Wells explained. “A novel mode of emergency DNA repair might indeed be discovered in the [iPSCs]. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”

The researchers plan to follow up this study with additional testing in humanized and genetic mouse models. They said they will attempt to improve embryonic development and post-birth fitness in FA-pathway-deficient mice with timed application of a CHK1 inhibitor.

The team will monitor the mice as they age and use genetic sequencing to screen for disease-causing mutations. And they will look for evidence of a DNA repair process (either novel or existing) in the FA-deficient mice.

Mick Bhatia, PhD

Photo courtesy of

McMaster University

Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).

Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.

And when both GSK-3β and GSK-3α are deleted, AML develops.

“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”

Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.

Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.

They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.

The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.

The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.

“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”

Mick Bhatia, PhD

Photo courtesy of

McMaster University

Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).

Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.

And when both GSK-3β and GSK-3α are deleted, AML develops.

“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”

Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.

Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.

They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.

The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.

The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.

“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”

Mick Bhatia, PhD

Photo courtesy of

McMaster University

Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).

Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.

And when both GSK-3β and GSK-3α are deleted, AML develops.

“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”

Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.

Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.

They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.

The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.

The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.

“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”

Hematopoietic stem cells

in the bone marrow

New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.

Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.

The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.

The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.

These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.

Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.

The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.

The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.

According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”

The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.

“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.

She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.

Hematopoietic stem cells

in the bone marrow

New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.

Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.

The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.

The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.

These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.

Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.

The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.

The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.

According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”

The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.

“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.

She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.

Hematopoietic stem cells

in the bone marrow

New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.

Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.

The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.

The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.

These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.

Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.

The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.

The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.

According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”

The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.

“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.

She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

X-ray of the hand of a patient

with Fanconi anemia

Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.

The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.

“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.

“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”

Dr May and his colleagues described the mutation in Nature Communications.

Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.

They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.

The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.

Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.

Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA has to be recalculated.

“Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors,” Dr May said. “Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it.”

X-ray of the hand of a patient

with Fanconi anemia

Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.

The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.

“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.

“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”

Dr May and his colleagues described the mutation in Nature Communications.

Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.

They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.

The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.

Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.

Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA has to be recalculated.

“Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors,” Dr May said. “Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it.”

X-ray of the hand of a patient

with Fanconi anemia

Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.

The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.

“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.

“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”

Dr May and his colleagues described the mutation in Nature Communications.

Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.

They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.

The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.

Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.

Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA has to be recalculated.

“Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors,” Dr May said. “Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it.”

Prescription medications

Photo courtesy of the CDC

ORLANDO, FL—In a small study, the cholesterol-lowering medication simvastatin reduced the frequency of vaso-occlusive pain in adults and children with sickle cell disease (SCD).

Overall, there was a 46% decrease in the frequency of vaso-occlusive pain after 3 months of treatment with simvastatin.

There was a slight overall decrease in the intensity of pain as well, but this was not statistically significant.

Still, investigators observed a decrease in biomarkers of inflammation and said the drug appeared to be safe for this patient population.

The team believes these preliminary data suggest the need to conduct a larger, randomized trial of simvastatin in SCD.

Carolyn C. Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California, presented the data at the 2015 ASH Annual Meeting (abstract 545).*

“Vaso-occlusive pain is a clinical hallmark and major cause of morbidity in sickle cell disease,” Dr Hoppe said. “Triggered by polymerization and hemolysis, vaso-occlusion involves multiple pathways.”

Similarly, although statins are best known for their cholesterol-inhibiting ability, they also inhibit oxidative stress and inflammation.

With this in mind, Dr Hoppe and her colleagues previously tested simvastatin in a phase 1 study of SCD patients who were 13 years of age or older.

The investigators found the safety profile to be acceptable, and they observed an improvement in biomarkers of inflammation. So they decided to carry out the current study.

This was a single-center, uncontrolled trial that enrolled SCD patients ages 10 and older. They received once-daily oral simvastatin (40 mg) for 3 months.

The primary outcome measure was the frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment.

Clinical laboratory studies and plasma biomarkers were evaluated at baseline, at 0.5, 1, 2, and 3 months during treatment, as well as 1 month after the discontinuation of simvastatin.

Results

Nineteen patients completed the study. They had a mean age of 19 (range, 10-34), and 13 were female. Seventeen had HbSS genotype, and 2 had S/β0 thalassemia. Ten patients were receiving hydroxyurea.

The simvastatin adherence rate was 85%, and the adherence to using the daily pain diary was 73%.

Dr Hoppe said there were no new safety issues or drug-related adverse events in this trial. There was no myalgia or myopathy. One subject did experience transient facial swelling that may have been drug-related.

The patients’ total cholesterol decreased by 20% from baseline. There was a significant decrease in both LDL and HDL cholesterol (P<0.001 for both).

Creatinine kinase remained stable during treatment, as did hemoglobin levels.

Dr Hoppe noted that the study was not designed to include an assessment of fetal hemoglobin, so she and her colleagues did not have data on that measure for all the patients, but the team did observe an increase in fetal hemoglobin levels from baseline among the patients who were receiving hydroxyurea.

The investigators observed a decrease from baseline in markers of hemolysis—absolute reticulocyte count (P=0.006) and total bilirubin (P=0.02).

Overall, there was a 46% decrease in the frequency of vaso-occlusive pain from baseline (P=0.005) and a 10% decrease in the intensity of pain (which was not significant).

There was a 59% decrease in hsCRP (P=0.003), an 18% decrease in sE-selectin (P=0.01), a 5% decrease in sICAM (P=0.03), and a 17% decrease in VEGF (P=0.05). There was no significant effect on plasma nitric oxide metabolites, sVCAM1, or P-selectin levels.

“These results are basically preliminary data to give clinical support for a larger, randomized trial of simvastatin to assess its clinical efficacy in SCD,” Dr Hoppe concluded.

She reported receiving research funding and consultancy payments from Eli Lilly and Company, and another investigator involved in this study is an employee of Pharmacyclics LLC.

*Data in the abstract differ from the data presented.

Prescription medications

Photo courtesy of the CDC

ORLANDO, FL—In a small study, the cholesterol-lowering medication simvastatin reduced the frequency of vaso-occlusive pain in adults and children with sickle cell disease (SCD).

Overall, there was a 46% decrease in the frequency of vaso-occlusive pain after 3 months of treatment with simvastatin.

There was a slight overall decrease in the intensity of pain as well, but this was not statistically significant.

Still, investigators observed a decrease in biomarkers of inflammation and said the drug appeared to be safe for this patient population.

The team believes these preliminary data suggest the need to conduct a larger, randomized trial of simvastatin in SCD.

Carolyn C. Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California, presented the data at the 2015 ASH Annual Meeting (abstract 545).*

“Vaso-occlusive pain is a clinical hallmark and major cause of morbidity in sickle cell disease,” Dr Hoppe said. “Triggered by polymerization and hemolysis, vaso-occlusion involves multiple pathways.”

Similarly, although statins are best known for their cholesterol-inhibiting ability, they also inhibit oxidative stress and inflammation.

With this in mind, Dr Hoppe and her colleagues previously tested simvastatin in a phase 1 study of SCD patients who were 13 years of age or older.

The investigators found the safety profile to be acceptable, and they observed an improvement in biomarkers of inflammation. So they decided to carry out the current study.

This was a single-center, uncontrolled trial that enrolled SCD patients ages 10 and older. They received once-daily oral simvastatin (40 mg) for 3 months.

The primary outcome measure was the frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment.

Clinical laboratory studies and plasma biomarkers were evaluated at baseline, at 0.5, 1, 2, and 3 months during treatment, as well as 1 month after the discontinuation of simvastatin.

Results

Nineteen patients completed the study. They had a mean age of 19 (range, 10-34), and 13 were female. Seventeen had HbSS genotype, and 2 had S/β0 thalassemia. Ten patients were receiving hydroxyurea.

The simvastatin adherence rate was 85%, and the adherence to using the daily pain diary was 73%.

Dr Hoppe said there were no new safety issues or drug-related adverse events in this trial. There was no myalgia or myopathy. One subject did experience transient facial swelling that may have been drug-related.

The patients’ total cholesterol decreased by 20% from baseline. There was a significant decrease in both LDL and HDL cholesterol (P<0.001 for both).

Creatinine kinase remained stable during treatment, as did hemoglobin levels.

Dr Hoppe noted that the study was not designed to include an assessment of fetal hemoglobin, so she and her colleagues did not have data on that measure for all the patients, but the team did observe an increase in fetal hemoglobin levels from baseline among the patients who were receiving hydroxyurea.

The investigators observed a decrease from baseline in markers of hemolysis—absolute reticulocyte count (P=0.006) and total bilirubin (P=0.02).

Overall, there was a 46% decrease in the frequency of vaso-occlusive pain from baseline (P=0.005) and a 10% decrease in the intensity of pain (which was not significant).

There was a 59% decrease in hsCRP (P=0.003), an 18% decrease in sE-selectin (P=0.01), a 5% decrease in sICAM (P=0.03), and a 17% decrease in VEGF (P=0.05). There was no significant effect on plasma nitric oxide metabolites, sVCAM1, or P-selectin levels.

“These results are basically preliminary data to give clinical support for a larger, randomized trial of simvastatin to assess its clinical efficacy in SCD,” Dr Hoppe concluded.

She reported receiving research funding and consultancy payments from Eli Lilly and Company, and another investigator involved in this study is an employee of Pharmacyclics LLC.

*Data in the abstract differ from the data presented.

Prescription medications

Photo courtesy of the CDC

ORLANDO, FL—In a small study, the cholesterol-lowering medication simvastatin reduced the frequency of vaso-occlusive pain in adults and children with sickle cell disease (SCD).

Overall, there was a 46% decrease in the frequency of vaso-occlusive pain after 3 months of treatment with simvastatin.

There was a slight overall decrease in the intensity of pain as well, but this was not statistically significant.

Still, investigators observed a decrease in biomarkers of inflammation and said the drug appeared to be safe for this patient population.

The team believes these preliminary data suggest the need to conduct a larger, randomized trial of simvastatin in SCD.

Carolyn C. Hoppe, MD, of UCSF Benioff Children’s Hospital Oakland in California, presented the data at the 2015 ASH Annual Meeting (abstract 545).*

“Vaso-occlusive pain is a clinical hallmark and major cause of morbidity in sickle cell disease,” Dr Hoppe said. “Triggered by polymerization and hemolysis, vaso-occlusion involves multiple pathways.”

Similarly, although statins are best known for their cholesterol-inhibiting ability, they also inhibit oxidative stress and inflammation.

With this in mind, Dr Hoppe and her colleagues previously tested simvastatin in a phase 1 study of SCD patients who were 13 years of age or older.

The investigators found the safety profile to be acceptable, and they observed an improvement in biomarkers of inflammation. So they decided to carry out the current study.

This was a single-center, uncontrolled trial that enrolled SCD patients ages 10 and older. They received once-daily oral simvastatin (40 mg) for 3 months.

The primary outcome measure was the frequency and intensity of vaso-occlusive pain, as recorded by daily electronic pain diaries, before and after simvastatin treatment.

Clinical laboratory studies and plasma biomarkers were evaluated at baseline, at 0.5, 1, 2, and 3 months during treatment, as well as 1 month after the discontinuation of simvastatin.

Results

Nineteen patients completed the study. They had a mean age of 19 (range, 10-34), and 13 were female. Seventeen had HbSS genotype, and 2 had S/β0 thalassemia. Ten patients were receiving hydroxyurea.

The simvastatin adherence rate was 85%, and the adherence to using the daily pain diary was 73%.

Dr Hoppe said there were no new safety issues or drug-related adverse events in this trial. There was no myalgia or myopathy. One subject did experience transient facial swelling that may have been drug-related.

The patients’ total cholesterol decreased by 20% from baseline. There was a significant decrease in both LDL and HDL cholesterol (P<0.001 for both).

Creatinine kinase remained stable during treatment, as did hemoglobin levels.

Dr Hoppe noted that the study was not designed to include an assessment of fetal hemoglobin, so she and her colleagues did not have data on that measure for all the patients, but the team did observe an increase in fetal hemoglobin levels from baseline among the patients who were receiving hydroxyurea.

The investigators observed a decrease from baseline in markers of hemolysis—absolute reticulocyte count (P=0.006) and total bilirubin (P=0.02).

Overall, there was a 46% decrease in the frequency of vaso-occlusive pain from baseline (P=0.005) and a 10% decrease in the intensity of pain (which was not significant).

There was a 59% decrease in hsCRP (P=0.003), an 18% decrease in sE-selectin (P=0.01), a 5% decrease in sICAM (P=0.03), and a 17% decrease in VEGF (P=0.05). There was no significant effect on plasma nitric oxide metabolites, sVCAM1, or P-selectin levels.

“These results are basically preliminary data to give clinical support for a larger, randomized trial of simvastatin to assess its clinical efficacy in SCD,” Dr Hoppe concluded.

She reported receiving research funding and consultancy payments from Eli Lilly and Company, and another investigator involved in this study is an employee of Pharmacyclics LLC.

*Data in the abstract differ from the data presented.

Red blood cells

A population-based study conducted in Germany has suggested a link between anemia and mild cognitive impairment (MCI).

Researchers found that subjects with anemia, defined as hemoglobin <13 g/dL in men and <12 g/dL in women, performed worse on cognitive tests than their nonanemic peers.

And MCI occurred almost twice as often in subjects with anemia than in subjects with normal hemoglobin levels.

This study was published in the Journal of Alzheimer’s Disease.

About MCI

MCI represents an intermediate and possibly modifiable stage between normal cognitive aging and dementia. Although individuals with MCI have an increased risk of developing dementia or Alzheimer’s disease, they can also remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia.

The following 4 criteria are used to diagnose MCI. First, subjects must report a decline in cognitive performance over the past 2 years. Second, they must show a cognitive impairment in objective cognitive tasks that is greater than one would expect taking their age and education into consideration.

Third, the impairment must not be as pronounced as in demented individuals since people with MCI can perform normal daily living activities or are only slightly impaired in carrying out complex instrumental functions. Fourth, the cognitive impairment has to be insufficient to fulfil criteria for dementia.

The concept of MCI distinguishes between amnestic MCI (aMCI) and non-amnestic MCI (naMCI). In the former, impairment in the memory domain is evident, most likely reflecting Alzheimer’s disease pathology. In the latter, impairment in non-memory domains is present, mainly reflecting vascular pathology but also frontotemporal dementia or dementia with Lewy bodies.

Study details

The Heinz Nixdorf Recall study is an observational, population-based, prospective study in which researchers examined 4814 subjects between 2000 and 2003. Subjects were 50 to 80 years of age and lived in the metropolitan Ruhr Area. Both genders were equally represented.

After 5 years, the researchers conducted a second examination with 92% of the subjects taking part. The publication includes cross-sectional results of the second examination.

First, 163 subjects with anemia and 3870 without anemia were included to compare their performance in all cognitive subtests.

The subjects took verbal memory tests, which were used to gauge immediate recall and delayed recall. They were also tested on executive functioning, which included problem-solving/speed of processing, verbal fluency, visual spatial organization, and the clock drawing test.

In the initial analysis, anemic subjects showed more pronounced cardiovascular risk profiles and lower cognitive performance in all administered cognitive subtests. After adjusting for age, anemic subjects showed a significantly lower performance in the immediate recall task (P=0.009) and the verbal fluency task (P=0.004).

Next, the researchers compared 579 subjects diagnosed with MCI—299 with aMCI and 280 with naMCI—to 1438 cognitively normal subjects to determine the association between anemia at follow-up and MCI.

The team found that MCI occurred more often in anemic than non-anemic subjects. The unadjusted odds ratio (OR) was 2.59 (P<0.001). The OR after adjustment for age, gender, and years of education was 2.15 (P=0.002).

In a third analysis, the researchers adjusted for the aforementioned variables as well as body mass index, high-sensitivity C-reactive protein, glomerular filtration rate, cholesterol, serum iron, hypertension, diabetes mellitus, history of coronary heart disease, history of stroke, history of cancer, APOE4, smoking, severe depressive symptoms, and use of antidepressants. The OR after adjustment for these factors was 1.92 (P=0.04).

Similar results were found for aMCI and naMCI. The researchers said this suggests that having a low hemoglobin level may contribute to cognitive impairment via different pathways.

The team believes that, overall, their study results indicate that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. They said the association between anemia and MCI has important clinical relevance because—depending on etiology—anemia can be treated effectively, and this might provide means to prevent or delay cognitive decline.

Red blood cells

A population-based study conducted in Germany has suggested a link between anemia and mild cognitive impairment (MCI).

Researchers found that subjects with anemia, defined as hemoglobin <13 g/dL in men and <12 g/dL in women, performed worse on cognitive tests than their nonanemic peers.

And MCI occurred almost twice as often in subjects with anemia than in subjects with normal hemoglobin levels.

This study was published in the Journal of Alzheimer’s Disease.

About MCI

MCI represents an intermediate and possibly modifiable stage between normal cognitive aging and dementia. Although individuals with MCI have an increased risk of developing dementia or Alzheimer’s disease, they can also remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia.

The following 4 criteria are used to diagnose MCI. First, subjects must report a decline in cognitive performance over the past 2 years. Second, they must show a cognitive impairment in objective cognitive tasks that is greater than one would expect taking their age and education into consideration.

Third, the impairment must not be as pronounced as in demented individuals since people with MCI can perform normal daily living activities or are only slightly impaired in carrying out complex instrumental functions. Fourth, the cognitive impairment has to be insufficient to fulfil criteria for dementia.

The concept of MCI distinguishes between amnestic MCI (aMCI) and non-amnestic MCI (naMCI). In the former, impairment in the memory domain is evident, most likely reflecting Alzheimer’s disease pathology. In the latter, impairment in non-memory domains is present, mainly reflecting vascular pathology but also frontotemporal dementia or dementia with Lewy bodies.

Study details

The Heinz Nixdorf Recall study is an observational, population-based, prospective study in which researchers examined 4814 subjects between 2000 and 2003. Subjects were 50 to 80 years of age and lived in the metropolitan Ruhr Area. Both genders were equally represented.

After 5 years, the researchers conducted a second examination with 92% of the subjects taking part. The publication includes cross-sectional results of the second examination.

First, 163 subjects with anemia and 3870 without anemia were included to compare their performance in all cognitive subtests.

The subjects took verbal memory tests, which were used to gauge immediate recall and delayed recall. They were also tested on executive functioning, which included problem-solving/speed of processing, verbal fluency, visual spatial organization, and the clock drawing test.

In the initial analysis, anemic subjects showed more pronounced cardiovascular risk profiles and lower cognitive performance in all administered cognitive subtests. After adjusting for age, anemic subjects showed a significantly lower performance in the immediate recall task (P=0.009) and the verbal fluency task (P=0.004).

Next, the researchers compared 579 subjects diagnosed with MCI—299 with aMCI and 280 with naMCI—to 1438 cognitively normal subjects to determine the association between anemia at follow-up and MCI.

The team found that MCI occurred more often in anemic than non-anemic subjects. The unadjusted odds ratio (OR) was 2.59 (P<0.001). The OR after adjustment for age, gender, and years of education was 2.15 (P=0.002).

In a third analysis, the researchers adjusted for the aforementioned variables as well as body mass index, high-sensitivity C-reactive protein, glomerular filtration rate, cholesterol, serum iron, hypertension, diabetes mellitus, history of coronary heart disease, history of stroke, history of cancer, APOE4, smoking, severe depressive symptoms, and use of antidepressants. The OR after adjustment for these factors was 1.92 (P=0.04).

Similar results were found for aMCI and naMCI. The researchers said this suggests that having a low hemoglobin level may contribute to cognitive impairment via different pathways.

The team believes that, overall, their study results indicate that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. They said the association between anemia and MCI has important clinical relevance because—depending on etiology—anemia can be treated effectively, and this might provide means to prevent or delay cognitive decline.

Red blood cells

A population-based study conducted in Germany has suggested a link between anemia and mild cognitive impairment (MCI).

Researchers found that subjects with anemia, defined as hemoglobin <13 g/dL in men and <12 g/dL in women, performed worse on cognitive tests than their nonanemic peers.

And MCI occurred almost twice as often in subjects with anemia than in subjects with normal hemoglobin levels.

This study was published in the Journal of Alzheimer’s Disease.

About MCI

MCI represents an intermediate and possibly modifiable stage between normal cognitive aging and dementia. Although individuals with MCI have an increased risk of developing dementia or Alzheimer’s disease, they can also remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia.

The following 4 criteria are used to diagnose MCI. First, subjects must report a decline in cognitive performance over the past 2 years. Second, they must show a cognitive impairment in objective cognitive tasks that is greater than one would expect taking their age and education into consideration.

Third, the impairment must not be as pronounced as in demented individuals since people with MCI can perform normal daily living activities or are only slightly impaired in carrying out complex instrumental functions. Fourth, the cognitive impairment has to be insufficient to fulfil criteria for dementia.

The concept of MCI distinguishes between amnestic MCI (aMCI) and non-amnestic MCI (naMCI). In the former, impairment in the memory domain is evident, most likely reflecting Alzheimer’s disease pathology. In the latter, impairment in non-memory domains is present, mainly reflecting vascular pathology but also frontotemporal dementia or dementia with Lewy bodies.

Study details

The Heinz Nixdorf Recall study is an observational, population-based, prospective study in which researchers examined 4814 subjects between 2000 and 2003. Subjects were 50 to 80 years of age and lived in the metropolitan Ruhr Area. Both genders were equally represented.

After 5 years, the researchers conducted a second examination with 92% of the subjects taking part. The publication includes cross-sectional results of the second examination.

First, 163 subjects with anemia and 3870 without anemia were included to compare their performance in all cognitive subtests.

The subjects took verbal memory tests, which were used to gauge immediate recall and delayed recall. They were also tested on executive functioning, which included problem-solving/speed of processing, verbal fluency, visual spatial organization, and the clock drawing test.

In the initial analysis, anemic subjects showed more pronounced cardiovascular risk profiles and lower cognitive performance in all administered cognitive subtests. After adjusting for age, anemic subjects showed a significantly lower performance in the immediate recall task (P=0.009) and the verbal fluency task (P=0.004).

Next, the researchers compared 579 subjects diagnosed with MCI—299 with aMCI and 280 with naMCI—to 1438 cognitively normal subjects to determine the association between anemia at follow-up and MCI.

The team found that MCI occurred more often in anemic than non-anemic subjects. The unadjusted odds ratio (OR) was 2.59 (P<0.001). The OR after adjustment for age, gender, and years of education was 2.15 (P=0.002).

In a third analysis, the researchers adjusted for the aforementioned variables as well as body mass index, high-sensitivity C-reactive protein, glomerular filtration rate, cholesterol, serum iron, hypertension, diabetes mellitus, history of coronary heart disease, history of stroke, history of cancer, APOE4, smoking, severe depressive symptoms, and use of antidepressants. The OR after adjustment for these factors was 1.92 (P=0.04).

Similar results were found for aMCI and naMCI. The researchers said this suggests that having a low hemoglobin level may contribute to cognitive impairment via different pathways.

The team believes that, overall, their study results indicate that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. They said the association between anemia and MCI has important clinical relevance because—depending on etiology—anemia can be treated effectively, and this might provide means to prevent or delay cognitive decline.

A sickled red blood cell

and a normal one

Image by Betty Pace

Preclinical research suggests a drug used to treat multiple myeloma (MM) might also prove effective in the treatment of sickle cell disease (SCD).

Researchers say this study is the first to reveal how the drug, pomalidomide, increases the production of fetal hemoglobin, which is known to interfere with the sickling of red blood cells.

“We knew the drug would make fetal hemoglobin, but we didn’t know to what extent or how,” said Lionel Blanc, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York.

He and his colleagues reported their findings in Blood.

The researchers’ in vitro experiments revealed that pomalidomide reverses γ-globin silencing during adult erythropoiesis, and the drug delays the maturation of early erythroid precursors without impairing terminal differentiation.

The team also found that pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis, the drug’s mechanism of action during erythropoiesis is independent of IKZF1 degradation, and pomalidomide partially reprograms adult erythroid progenitors to a fetal-like state.

Finally, the researchers discovered that pomalidomide’s mechanism of action is conserved in cells from SCD patients, and treatment with pomalidomide leads to γ-globin production in MM patients.

“We can also say something else—that hydroxyurea, the only FDA-approved drug for sickle cell anemia, was less effective than pomalidomide and appeared to act through a different mechanism of action,” Dr Blanc said.

“The current therapy is good, but not everyone responds equally to hydroxyurea, and what we hope with pomalidomide is to improve this.”

Dr Blanc and his colleagues plan to launch a clinical trial in the near future to test pomalidomide in young adults with SCD.

A sickled red blood cell

and a normal one

Image by Betty Pace

Preclinical research suggests a drug used to treat multiple myeloma (MM) might also prove effective in the treatment of sickle cell disease (SCD).

Researchers say this study is the first to reveal how the drug, pomalidomide, increases the production of fetal hemoglobin, which is known to interfere with the sickling of red blood cells.

“We knew the drug would make fetal hemoglobin, but we didn’t know to what extent or how,” said Lionel Blanc, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York.

He and his colleagues reported their findings in Blood.

The researchers’ in vitro experiments revealed that pomalidomide reverses γ-globin silencing during adult erythropoiesis, and the drug delays the maturation of early erythroid precursors without impairing terminal differentiation.

The team also found that pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis, the drug’s mechanism of action during erythropoiesis is independent of IKZF1 degradation, and pomalidomide partially reprograms adult erythroid progenitors to a fetal-like state.

Finally, the researchers discovered that pomalidomide’s mechanism of action is conserved in cells from SCD patients, and treatment with pomalidomide leads to γ-globin production in MM patients.

“We can also say something else—that hydroxyurea, the only FDA-approved drug for sickle cell anemia, was less effective than pomalidomide and appeared to act through a different mechanism of action,” Dr Blanc said.

“The current therapy is good, but not everyone responds equally to hydroxyurea, and what we hope with pomalidomide is to improve this.”

Dr Blanc and his colleagues plan to launch a clinical trial in the near future to test pomalidomide in young adults with SCD.

A sickled red blood cell

and a normal one

Image by Betty Pace

Preclinical research suggests a drug used to treat multiple myeloma (MM) might also prove effective in the treatment of sickle cell disease (SCD).

Researchers say this study is the first to reveal how the drug, pomalidomide, increases the production of fetal hemoglobin, which is known to interfere with the sickling of red blood cells.

“We knew the drug would make fetal hemoglobin, but we didn’t know to what extent or how,” said Lionel Blanc, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York.

He and his colleagues reported their findings in Blood.

The researchers’ in vitro experiments revealed that pomalidomide reverses γ-globin silencing during adult erythropoiesis, and the drug delays the maturation of early erythroid precursors without impairing terminal differentiation.

The team also found that pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis, the drug’s mechanism of action during erythropoiesis is independent of IKZF1 degradation, and pomalidomide partially reprograms adult erythroid progenitors to a fetal-like state.

Finally, the researchers discovered that pomalidomide’s mechanism of action is conserved in cells from SCD patients, and treatment with pomalidomide leads to γ-globin production in MM patients.

“We can also say something else—that hydroxyurea, the only FDA-approved drug for sickle cell anemia, was less effective than pomalidomide and appeared to act through a different mechanism of action,” Dr Blanc said.

“The current therapy is good, but not everyone responds equally to hydroxyurea, and what we hope with pomalidomide is to improve this.”

Dr Blanc and his colleagues plan to launch a clinical trial in the near future to test pomalidomide in young adults with SCD.

Bone marrow harvest

Photo by Chad McNeeley

ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).

However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.

Patient age and stem cell source were both independently associated with event-free and overall survival.

These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.

Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).

The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).

About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.

The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.

Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.

A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).

Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).

Results

The median follow-up was 45 months (range, 1-325).

At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.

Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.

Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.

Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.

The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.

The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.

Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.

Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.

Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.

“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”

She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.

*Data in the abstract differ from the presentation.

Bone marrow harvest

Photo by Chad McNeeley

ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).

However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.

Patient age and stem cell source were both independently associated with event-free and overall survival.

These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.

Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).

The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).

About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.

The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.

Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.

A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).

Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).

Results

The median follow-up was 45 months (range, 1-325).

At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.

Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.

Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.

Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.

The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.

The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.

Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.

Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.

Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.

“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”

She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.

*Data in the abstract differ from the presentation.

Bone marrow harvest

Photo by Chad McNeeley

ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).

However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.

Patient age and stem cell source were both independently associated with event-free and overall survival.

These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.

Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).

The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).

About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.

The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.

Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.

A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).

Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).

Results

The median follow-up was 45 months (range, 1-325).

At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.

Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.

Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.

Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.

The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.

The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.

Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.

Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.

Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.

“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”

She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.

*Data in the abstract differ from the presentation.