Anemia

CMV infection

Small studies have suggested that early cytomegalovirus (CMV) reactivation may protect against leukemia relapse and even death after hematopoietic stem cell transplant.

However, a new study, based on data from about 9500 patients, suggests otherwise.

Results showed no association between CMV reactivation and relapse but suggested CMV reactivation increases the risk of non-relapse mortality.

Researchers reported these findings in Blood.

“The original purpose of the study was to confirm that CMV infection may prevent leukemia relapse, prevent death, and become a major therapeutic tool for improving patient survival rates,” said study author Pierre Teira, MD, of the University of Montreal in Quebec, Canada.

“However, we found the exact opposite. Our results clearly show that . . . the virus not only does not prevent leukemia relapse [it] also remains a major factor associated with the risk of death. Monitoring of CMV after transplantation remains a priority for patients.”

For this study, Dr Teira and his colleagues analyzed data from 9469 patients who received a transplant between 2003 and 2010.

The patients had acute myeloid leukemia (AML, n=5310), acute lymphoblastic leukemia (ALL, n=1883), chronic myeloid leukemia (CML, n=1079), or myelodysplastic syndromes (MDS, n=1197).

The median time to initial CMV reactivation was 41 days (range, 1-362 days).

The researchers found no significant association between CMV reactivation and disease relapse for AML (P=0.60), ALL (P=0.08), CML (P=0.94), or MDS (P=0.58).

However, CMV reactivation was associated with a significantly higher risk of nonrelapse mortality for AML (P<0.0001), ALL (P<0.0001), CML (P=0.0004), and MDS (P=0.0002).

Therefore, CMV reactivation was associated with significantly lower overall survival for AML (P<0.0001), ALL (P<0.0001), CML (P=0.0005), and MDS (P=0.003).

“Deaths due to uncontrolled CMV reactivation are virtually zero in this study, so uncontrolled CMV reactivation is not what reduces survival rates after transplantation,” Dr Teira noted. “The link between this common virus and increased risk of death remains a biological mystery.”

One possible explanation is that CMV decreases the ability of the patient’s immune system to fight against other types of infection. This is supported by the fact that death rates from infections other than CMV are higher in patients infected with CMV or patients whose donors were.

For researchers, the next step is therefore to verify whether the latest generation of anti-CMV treatments can prevent both reactivation of the virus and weakening of the patient’s immune system against other types of infection in the presence of CMV infection.

“CMV has a complex impact on the outcomes for transplant patients, and, each year, more than 30,000 patients around the world receive bone marrow transplants from donors,” Dr Teira said.

“It is therefore essential for future research to better understand the role played by CMV after bone marrow transplantation and improve the chances of success of the transplant. This will help to better choose the right donor for the right patient.”

CMV infection

Small studies have suggested that early cytomegalovirus (CMV) reactivation may protect against leukemia relapse and even death after hematopoietic stem cell transplant.

However, a new study, based on data from about 9500 patients, suggests otherwise.

Results showed no association between CMV reactivation and relapse but suggested CMV reactivation increases the risk of non-relapse mortality.

Researchers reported these findings in Blood.

“The original purpose of the study was to confirm that CMV infection may prevent leukemia relapse, prevent death, and become a major therapeutic tool for improving patient survival rates,” said study author Pierre Teira, MD, of the University of Montreal in Quebec, Canada.

“However, we found the exact opposite. Our results clearly show that . . . the virus not only does not prevent leukemia relapse [it] also remains a major factor associated with the risk of death. Monitoring of CMV after transplantation remains a priority for patients.”

For this study, Dr Teira and his colleagues analyzed data from 9469 patients who received a transplant between 2003 and 2010.

The patients had acute myeloid leukemia (AML, n=5310), acute lymphoblastic leukemia (ALL, n=1883), chronic myeloid leukemia (CML, n=1079), or myelodysplastic syndromes (MDS, n=1197).

The median time to initial CMV reactivation was 41 days (range, 1-362 days).

The researchers found no significant association between CMV reactivation and disease relapse for AML (P=0.60), ALL (P=0.08), CML (P=0.94), or MDS (P=0.58).

However, CMV reactivation was associated with a significantly higher risk of nonrelapse mortality for AML (P<0.0001), ALL (P<0.0001), CML (P=0.0004), and MDS (P=0.0002).

Therefore, CMV reactivation was associated with significantly lower overall survival for AML (P<0.0001), ALL (P<0.0001), CML (P=0.0005), and MDS (P=0.003).

“Deaths due to uncontrolled CMV reactivation are virtually zero in this study, so uncontrolled CMV reactivation is not what reduces survival rates after transplantation,” Dr Teira noted. “The link between this common virus and increased risk of death remains a biological mystery.”

One possible explanation is that CMV decreases the ability of the patient’s immune system to fight against other types of infection. This is supported by the fact that death rates from infections other than CMV are higher in patients infected with CMV or patients whose donors were.

For researchers, the next step is therefore to verify whether the latest generation of anti-CMV treatments can prevent both reactivation of the virus and weakening of the patient’s immune system against other types of infection in the presence of CMV infection.

“CMV has a complex impact on the outcomes for transplant patients, and, each year, more than 30,000 patients around the world receive bone marrow transplants from donors,” Dr Teira said.

“It is therefore essential for future research to better understand the role played by CMV after bone marrow transplantation and improve the chances of success of the transplant. This will help to better choose the right donor for the right patient.”

CMV infection

Small studies have suggested that early cytomegalovirus (CMV) reactivation may protect against leukemia relapse and even death after hematopoietic stem cell transplant.

However, a new study, based on data from about 9500 patients, suggests otherwise.

Results showed no association between CMV reactivation and relapse but suggested CMV reactivation increases the risk of non-relapse mortality.

Researchers reported these findings in Blood.

“The original purpose of the study was to confirm that CMV infection may prevent leukemia relapse, prevent death, and become a major therapeutic tool for improving patient survival rates,” said study author Pierre Teira, MD, of the University of Montreal in Quebec, Canada.

“However, we found the exact opposite. Our results clearly show that . . . the virus not only does not prevent leukemia relapse [it] also remains a major factor associated with the risk of death. Monitoring of CMV after transplantation remains a priority for patients.”

For this study, Dr Teira and his colleagues analyzed data from 9469 patients who received a transplant between 2003 and 2010.

The patients had acute myeloid leukemia (AML, n=5310), acute lymphoblastic leukemia (ALL, n=1883), chronic myeloid leukemia (CML, n=1079), or myelodysplastic syndromes (MDS, n=1197).

The median time to initial CMV reactivation was 41 days (range, 1-362 days).

The researchers found no significant association between CMV reactivation and disease relapse for AML (P=0.60), ALL (P=0.08), CML (P=0.94), or MDS (P=0.58).

However, CMV reactivation was associated with a significantly higher risk of nonrelapse mortality for AML (P<0.0001), ALL (P<0.0001), CML (P=0.0004), and MDS (P=0.0002).

Therefore, CMV reactivation was associated with significantly lower overall survival for AML (P<0.0001), ALL (P<0.0001), CML (P=0.0005), and MDS (P=0.003).

“Deaths due to uncontrolled CMV reactivation are virtually zero in this study, so uncontrolled CMV reactivation is not what reduces survival rates after transplantation,” Dr Teira noted. “The link between this common virus and increased risk of death remains a biological mystery.”

One possible explanation is that CMV decreases the ability of the patient’s immune system to fight against other types of infection. This is supported by the fact that death rates from infections other than CMV are higher in patients infected with CMV or patients whose donors were.

For researchers, the next step is therefore to verify whether the latest generation of anti-CMV treatments can prevent both reactivation of the virus and weakening of the patient’s immune system against other types of infection in the presence of CMV infection.

“CMV has a complex impact on the outcomes for transplant patients, and, each year, more than 30,000 patients around the world receive bone marrow transplants from donors,” Dr Teira said.

“It is therefore essential for future research to better understand the role played by CMV after bone marrow transplantation and improve the chances of success of the transplant. This will help to better choose the right donor for the right patient.”

Uwe Platzbecker, MD

COPENHAGEN—Results from a pair of phase 2 trials suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS).

In a 3-month base study, 51% of patients treated with luspatercept had an erythroid response, and 35% achieved transfusion independence.

In an ongoing extension study, 81% of luspatercept-treated patients have had an erythroid response, and 50% have achieved transfusion independence.

The majority of adverse events in both trials were grade 1 and 2.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S131*). The studies were sponsored by Acceleron Pharma, Inc.

Luspatercept (formerly ACE-536) is a modified activin receptor type IIB fusion protein that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron and Celgene are developing luspatercept to treat anemia in patients with rare blood disorders.

The phase 2 base study was a dose-escalation trial in which MDS patients received luspatercept for 3 months. In the ongoing extension study, patients from the base study are receiving luspatercept for an additional 24 months.

In both studies, patients with high transfusion burden (≥4 RBC units/8 weeks) and those with low transfusion burden (<4 RBC units/8 weeks) received luspatercept once every 3 weeks.

Base study

This study included 58 patients with a median age of 71.5 (range, 27-90). Their median time since diagnosis was 2.4 years (range, 0-14). Seventeen percent of patients had prior lenalidomide treatment, and 66% had previously received erythropoiesis-stimulating agents (ESAs).

In patients with low transfusion burden (n=19), the median hemoglobin at baseline was 8.7 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=39), the median number of RBC units transfused per 8 weeks was 6 (range, 4-18).

Patients received luspatercept subcutaneously every 3 weeks for up to 5 doses. The study included 7 dose-escalation cohorts (n=27, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, 1.0 to 1.75 mg/kg).

The primary outcome measure was the proportion of patients who had an erythroid response. In non-transfusion-dependent patients, an erythroid response was defined as a hemoglobin increase of at least 1.5 g/dL from baseline for at least 14 days.

In transfusion-dependent patients, an erythroid response was defined as a reduction of at least 4 RBC units transfused or a reduction of at least 50% of RBC units transfused compared to pretreatment.

Fifty-one percent (25/49) of patients treated at the higher dose levels had an erythroid response. And 35% (14/40) of transfused patients treated at the higher dose levels were transfusion independent for at least 8 weeks.

Extension study

This study includes 32 patients with a median age of 71.5 (range, 29-90). Their median time since diagnosis was 2.9 years (range, 0-14). Nineteen percent of patients had prior lenalidomide treatment, and 59% had previously received ESAs.

In patients with low transfusion burden (n=13), the median hemoglobin at baseline was 8.5 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=19), the median number of RBC units transfused per 8 weeks was 6 (range, 4-14).

In this ongoing study, patients are receiving luspatercept (1.0 to 1.75 mg/kg) subcutaneously every 3 weeks for an additional 24 months.

At last follow-up (March 4, 2016), 81% (26/32) of patients had an erythroid response. And 50% (11/22) of patients who were transfused prior to study initiation achieved transfusion independence for at least 8 weeks (range, 9-80+ weeks).

Dr Platzbecker noted that, in both studies, erythroid responses were observed whether or not patients previously received ESAs and regardless of patients’ baseline erythropoietin levels.

Safety

There were three grade 3 adverse events that were possibly or probably related to luspatercept—an increase in blast cell count, myalgia, and worsening of general condition.

Adverse events that were possibly or probably related to luspatercept and occurred in at least 2 patients were fatigue (7%, n=4), bone pain (5%, n=3), diarrhea (5%, n=3), myalgia (5%, n=3), headache (3%, n=2), hypertension (3%, n=2), and injection site erythema (3%, n=2).

Dr Platzbecker said luspatercept was generally safe and well-tolerated in these studies. And the results of these trials supported the initiation of a phase 3 study (MEDALIST, NCT02631070) in patients with lower-risk MDS.

*Data in the abstract differ from data presented at the meeting.

Uwe Platzbecker, MD

COPENHAGEN—Results from a pair of phase 2 trials suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS).

In a 3-month base study, 51% of patients treated with luspatercept had an erythroid response, and 35% achieved transfusion independence.

In an ongoing extension study, 81% of luspatercept-treated patients have had an erythroid response, and 50% have achieved transfusion independence.

The majority of adverse events in both trials were grade 1 and 2.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S131*). The studies were sponsored by Acceleron Pharma, Inc.

Luspatercept (formerly ACE-536) is a modified activin receptor type IIB fusion protein that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron and Celgene are developing luspatercept to treat anemia in patients with rare blood disorders.

The phase 2 base study was a dose-escalation trial in which MDS patients received luspatercept for 3 months. In the ongoing extension study, patients from the base study are receiving luspatercept for an additional 24 months.

In both studies, patients with high transfusion burden (≥4 RBC units/8 weeks) and those with low transfusion burden (<4 RBC units/8 weeks) received luspatercept once every 3 weeks.

Base study

This study included 58 patients with a median age of 71.5 (range, 27-90). Their median time since diagnosis was 2.4 years (range, 0-14). Seventeen percent of patients had prior lenalidomide treatment, and 66% had previously received erythropoiesis-stimulating agents (ESAs).

In patients with low transfusion burden (n=19), the median hemoglobin at baseline was 8.7 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=39), the median number of RBC units transfused per 8 weeks was 6 (range, 4-18).

Patients received luspatercept subcutaneously every 3 weeks for up to 5 doses. The study included 7 dose-escalation cohorts (n=27, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, 1.0 to 1.75 mg/kg).

The primary outcome measure was the proportion of patients who had an erythroid response. In non-transfusion-dependent patients, an erythroid response was defined as a hemoglobin increase of at least 1.5 g/dL from baseline for at least 14 days.

In transfusion-dependent patients, an erythroid response was defined as a reduction of at least 4 RBC units transfused or a reduction of at least 50% of RBC units transfused compared to pretreatment.

Fifty-one percent (25/49) of patients treated at the higher dose levels had an erythroid response. And 35% (14/40) of transfused patients treated at the higher dose levels were transfusion independent for at least 8 weeks.

Extension study

This study includes 32 patients with a median age of 71.5 (range, 29-90). Their median time since diagnosis was 2.9 years (range, 0-14). Nineteen percent of patients had prior lenalidomide treatment, and 59% had previously received ESAs.

In patients with low transfusion burden (n=13), the median hemoglobin at baseline was 8.5 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=19), the median number of RBC units transfused per 8 weeks was 6 (range, 4-14).

In this ongoing study, patients are receiving luspatercept (1.0 to 1.75 mg/kg) subcutaneously every 3 weeks for an additional 24 months.

At last follow-up (March 4, 2016), 81% (26/32) of patients had an erythroid response. And 50% (11/22) of patients who were transfused prior to study initiation achieved transfusion independence for at least 8 weeks (range, 9-80+ weeks).

Dr Platzbecker noted that, in both studies, erythroid responses were observed whether or not patients previously received ESAs and regardless of patients’ baseline erythropoietin levels.

Safety

There were three grade 3 adverse events that were possibly or probably related to luspatercept—an increase in blast cell count, myalgia, and worsening of general condition.

Adverse events that were possibly or probably related to luspatercept and occurred in at least 2 patients were fatigue (7%, n=4), bone pain (5%, n=3), diarrhea (5%, n=3), myalgia (5%, n=3), headache (3%, n=2), hypertension (3%, n=2), and injection site erythema (3%, n=2).

Dr Platzbecker said luspatercept was generally safe and well-tolerated in these studies. And the results of these trials supported the initiation of a phase 3 study (MEDALIST, NCT02631070) in patients with lower-risk MDS.

*Data in the abstract differ from data presented at the meeting.

Uwe Platzbecker, MD

COPENHAGEN—Results from a pair of phase 2 trials suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS).

In a 3-month base study, 51% of patients treated with luspatercept had an erythroid response, and 35% achieved transfusion independence.

In an ongoing extension study, 81% of luspatercept-treated patients have had an erythroid response, and 50% have achieved transfusion independence.

The majority of adverse events in both trials were grade 1 and 2.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S131*). The studies were sponsored by Acceleron Pharma, Inc.

Luspatercept (formerly ACE-536) is a modified activin receptor type IIB fusion protein that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron and Celgene are developing luspatercept to treat anemia in patients with rare blood disorders.

The phase 2 base study was a dose-escalation trial in which MDS patients received luspatercept for 3 months. In the ongoing extension study, patients from the base study are receiving luspatercept for an additional 24 months.

In both studies, patients with high transfusion burden (≥4 RBC units/8 weeks) and those with low transfusion burden (<4 RBC units/8 weeks) received luspatercept once every 3 weeks.

Base study

This study included 58 patients with a median age of 71.5 (range, 27-90). Their median time since diagnosis was 2.4 years (range, 0-14). Seventeen percent of patients had prior lenalidomide treatment, and 66% had previously received erythropoiesis-stimulating agents (ESAs).

In patients with low transfusion burden (n=19), the median hemoglobin at baseline was 8.7 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=39), the median number of RBC units transfused per 8 weeks was 6 (range, 4-18).

Patients received luspatercept subcutaneously every 3 weeks for up to 5 doses. The study included 7 dose-escalation cohorts (n=27, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, 1.0 to 1.75 mg/kg).

The primary outcome measure was the proportion of patients who had an erythroid response. In non-transfusion-dependent patients, an erythroid response was defined as a hemoglobin increase of at least 1.5 g/dL from baseline for at least 14 days.

In transfusion-dependent patients, an erythroid response was defined as a reduction of at least 4 RBC units transfused or a reduction of at least 50% of RBC units transfused compared to pretreatment.

Fifty-one percent (25/49) of patients treated at the higher dose levels had an erythroid response. And 35% (14/40) of transfused patients treated at the higher dose levels were transfusion independent for at least 8 weeks.

Extension study

This study includes 32 patients with a median age of 71.5 (range, 29-90). Their median time since diagnosis was 2.9 years (range, 0-14). Nineteen percent of patients had prior lenalidomide treatment, and 59% had previously received ESAs.

In patients with low transfusion burden (n=13), the median hemoglobin at baseline was 8.5 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=19), the median number of RBC units transfused per 8 weeks was 6 (range, 4-14).

In this ongoing study, patients are receiving luspatercept (1.0 to 1.75 mg/kg) subcutaneously every 3 weeks for an additional 24 months.

At last follow-up (March 4, 2016), 81% (26/32) of patients had an erythroid response. And 50% (11/22) of patients who were transfused prior to study initiation achieved transfusion independence for at least 8 weeks (range, 9-80+ weeks).

Dr Platzbecker noted that, in both studies, erythroid responses were observed whether or not patients previously received ESAs and regardless of patients’ baseline erythropoietin levels.

Safety

There were three grade 3 adverse events that were possibly or probably related to luspatercept—an increase in blast cell count, myalgia, and worsening of general condition.

Adverse events that were possibly or probably related to luspatercept and occurred in at least 2 patients were fatigue (7%, n=4), bone pain (5%, n=3), diarrhea (5%, n=3), myalgia (5%, n=3), headache (3%, n=2), hypertension (3%, n=2), and injection site erythema (3%, n=2).

Dr Platzbecker said luspatercept was generally safe and well-tolerated in these studies. And the results of these trials supported the initiation of a phase 3 study (MEDALIST, NCT02631070) in patients with lower-risk MDS.

*Data in the abstract differ from data presented at the meeting.

A sickled red blood cell

and a normal one

Image by Betty Pace

Results of a small study suggest that long-term opioid treatment may not be the best option for pain management in adults with sickle cell disease (SCD).

The study showed that patients who received opioids long-term often fared worse in measures of pain, fatigue, and curtailed daily activities than patients who were not on long-term opioids.

Researchers reported these findings in the American Journal of Preventive Medicine.

“We need to be careful and skeptical about giving increasing doses of opioids to patients with sickle cell disease who are in chronic pain if it isn’t effective,” said study author C. Patrick Carroll, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“Too little is known about the effects of long-term opioid management of chronic pain.”

For this study, Dr Carroll and his colleagues enrolled 83 SCD patients—57 women and 26 men. All were 18 and older, and their average age was 39.

Twenty-nine of the patients had been prescribed daily, long-acting opioids to manage their pain. The remaining 54 patients weren’t on long-term opioids.

The patients filled out daily electronic pain diaries for 90 days. Self-reported levels of pain, physical activity, fatigue, and pain-related daily activity interference were recorded, along with self-reported levels of pain relief and medication satisfaction on a scale of 0 to 100.

Crises, pain, and fatigue

The proportion of days in vaso-occlusive crisis was significantly higher for patients who were on long-term opioid therapy than for those who were not—29% and 11.9%, respectively (P<0.01).

Patients on long-term opioids also reported significantly higher levels of crisis pain—60.6 and 41.0, respectively (P<0.001)—and non-crisis pain—34.5 and 10.3, respectively (P<0.001).

Patients on long-term opioid therapy had higher levels of pain-related activity interference, both on non-crisis days—24.9 and 7.4, respectively (P<0.001)—and crisis days—56.7 and 37.7, respectively (P<0.01).

And patients on long-term opioid therapy had higher levels of fatigue on non-crisis days—49.7 and 27.0, respectively (P<0.001)—and crisis days—66.1 and 53.0, respectively (P<0.05).

Central sensitization

The researchers also performed some standard measures of pain processing on the test subjects, which measured and averaged variables such as how intensely participants experienced unpleasant heat and pressure.

The team was particularly interested in the phenomenon of central sensitization, in which the central nervous system amplifies painful sensations.

Central sensitization may be one way that opioids can increase pain sensitivity, and it also may play a role in how SCD causes chronic pain, Dr Carroll said.

For example, one such measure of central sensitization uses repeated pokes from a mildly painful stimulus in succession. In people who have this hypersensitization, each poke is perceived as more intense than the last because the nervous system becomes progressively more sensitive to the pain.

Combining the data from several measures of central sensitization, the researchers used a scoring system that sets a normal measurement at 0 and rates how abnormal something is by how far the values move away from 0. They calculated a central sensitization index for patients on long-term opioids and those not taking them.

Overall, patients on long-term opioid therapy showed higher levels of central sensitization, with an index of 0.34, than those who were not on opioids, with an index of -0.10.

In patients who were not on long-term opioid therapy, the level of central sensitization correlated with the level of non-crisis pain. However, in patients who were taking long-term opioid therapy and also had higher levels of central sensitization and clinical pain, the correlation essentially vanished.

Dr Carroll said this was surprising and suggests the mechanisms of pain in SCD patients on long-term opioid therapy may be different from patients who don’t take daily opioids for pain.

Dr Carroll cautioned that this work is preliminary and should not lead to the discontinuation of long-term opioid therapy in SCD patients.

“We need to better understand how long-term opioid use affects pain sensitization and determine if certain people are more sensitive to these effects so we can prescribe the best treatment option for each individual patient,” Dr Carroll said. “We also need to learn more about how sickle cell disease may sensitize the nervous system.”

A sickled red blood cell

and a normal one

Image by Betty Pace

Results of a small study suggest that long-term opioid treatment may not be the best option for pain management in adults with sickle cell disease (SCD).

The study showed that patients who received opioids long-term often fared worse in measures of pain, fatigue, and curtailed daily activities than patients who were not on long-term opioids.

Researchers reported these findings in the American Journal of Preventive Medicine.

“We need to be careful and skeptical about giving increasing doses of opioids to patients with sickle cell disease who are in chronic pain if it isn’t effective,” said study author C. Patrick Carroll, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“Too little is known about the effects of long-term opioid management of chronic pain.”

For this study, Dr Carroll and his colleagues enrolled 83 SCD patients—57 women and 26 men. All were 18 and older, and their average age was 39.

Twenty-nine of the patients had been prescribed daily, long-acting opioids to manage their pain. The remaining 54 patients weren’t on long-term opioids.

The patients filled out daily electronic pain diaries for 90 days. Self-reported levels of pain, physical activity, fatigue, and pain-related daily activity interference were recorded, along with self-reported levels of pain relief and medication satisfaction on a scale of 0 to 100.

Crises, pain, and fatigue

The proportion of days in vaso-occlusive crisis was significantly higher for patients who were on long-term opioid therapy than for those who were not—29% and 11.9%, respectively (P<0.01).

Patients on long-term opioids also reported significantly higher levels of crisis pain—60.6 and 41.0, respectively (P<0.001)—and non-crisis pain—34.5 and 10.3, respectively (P<0.001).

Patients on long-term opioid therapy had higher levels of pain-related activity interference, both on non-crisis days—24.9 and 7.4, respectively (P<0.001)—and crisis days—56.7 and 37.7, respectively (P<0.01).

And patients on long-term opioid therapy had higher levels of fatigue on non-crisis days—49.7 and 27.0, respectively (P<0.001)—and crisis days—66.1 and 53.0, respectively (P<0.05).

Central sensitization

The researchers also performed some standard measures of pain processing on the test subjects, which measured and averaged variables such as how intensely participants experienced unpleasant heat and pressure.

The team was particularly interested in the phenomenon of central sensitization, in which the central nervous system amplifies painful sensations.

Central sensitization may be one way that opioids can increase pain sensitivity, and it also may play a role in how SCD causes chronic pain, Dr Carroll said.

For example, one such measure of central sensitization uses repeated pokes from a mildly painful stimulus in succession. In people who have this hypersensitization, each poke is perceived as more intense than the last because the nervous system becomes progressively more sensitive to the pain.

Combining the data from several measures of central sensitization, the researchers used a scoring system that sets a normal measurement at 0 and rates how abnormal something is by how far the values move away from 0. They calculated a central sensitization index for patients on long-term opioids and those not taking them.

Overall, patients on long-term opioid therapy showed higher levels of central sensitization, with an index of 0.34, than those who were not on opioids, with an index of -0.10.

In patients who were not on long-term opioid therapy, the level of central sensitization correlated with the level of non-crisis pain. However, in patients who were taking long-term opioid therapy and also had higher levels of central sensitization and clinical pain, the correlation essentially vanished.

Dr Carroll said this was surprising and suggests the mechanisms of pain in SCD patients on long-term opioid therapy may be different from patients who don’t take daily opioids for pain.

Dr Carroll cautioned that this work is preliminary and should not lead to the discontinuation of long-term opioid therapy in SCD patients.

“We need to better understand how long-term opioid use affects pain sensitization and determine if certain people are more sensitive to these effects so we can prescribe the best treatment option for each individual patient,” Dr Carroll said. “We also need to learn more about how sickle cell disease may sensitize the nervous system.”

A sickled red blood cell

and a normal one

Image by Betty Pace

Results of a small study suggest that long-term opioid treatment may not be the best option for pain management in adults with sickle cell disease (SCD).

The study showed that patients who received opioids long-term often fared worse in measures of pain, fatigue, and curtailed daily activities than patients who were not on long-term opioids.

Researchers reported these findings in the American Journal of Preventive Medicine.

“We need to be careful and skeptical about giving increasing doses of opioids to patients with sickle cell disease who are in chronic pain if it isn’t effective,” said study author C. Patrick Carroll, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“Too little is known about the effects of long-term opioid management of chronic pain.”

For this study, Dr Carroll and his colleagues enrolled 83 SCD patients—57 women and 26 men. All were 18 and older, and their average age was 39.

Twenty-nine of the patients had been prescribed daily, long-acting opioids to manage their pain. The remaining 54 patients weren’t on long-term opioids.

The patients filled out daily electronic pain diaries for 90 days. Self-reported levels of pain, physical activity, fatigue, and pain-related daily activity interference were recorded, along with self-reported levels of pain relief and medication satisfaction on a scale of 0 to 100.

Crises, pain, and fatigue

The proportion of days in vaso-occlusive crisis was significantly higher for patients who were on long-term opioid therapy than for those who were not—29% and 11.9%, respectively (P<0.01).

Patients on long-term opioids also reported significantly higher levels of crisis pain—60.6 and 41.0, respectively (P<0.001)—and non-crisis pain—34.5 and 10.3, respectively (P<0.001).

Patients on long-term opioid therapy had higher levels of pain-related activity interference, both on non-crisis days—24.9 and 7.4, respectively (P<0.001)—and crisis days—56.7 and 37.7, respectively (P<0.01).

And patients on long-term opioid therapy had higher levels of fatigue on non-crisis days—49.7 and 27.0, respectively (P<0.001)—and crisis days—66.1 and 53.0, respectively (P<0.05).

Central sensitization

The researchers also performed some standard measures of pain processing on the test subjects, which measured and averaged variables such as how intensely participants experienced unpleasant heat and pressure.

The team was particularly interested in the phenomenon of central sensitization, in which the central nervous system amplifies painful sensations.

Central sensitization may be one way that opioids can increase pain sensitivity, and it also may play a role in how SCD causes chronic pain, Dr Carroll said.

For example, one such measure of central sensitization uses repeated pokes from a mildly painful stimulus in succession. In people who have this hypersensitization, each poke is perceived as more intense than the last because the nervous system becomes progressively more sensitive to the pain.

Combining the data from several measures of central sensitization, the researchers used a scoring system that sets a normal measurement at 0 and rates how abnormal something is by how far the values move away from 0. They calculated a central sensitization index for patients on long-term opioids and those not taking them.

Overall, patients on long-term opioid therapy showed higher levels of central sensitization, with an index of 0.34, than those who were not on opioids, with an index of -0.10.

In patients who were not on long-term opioid therapy, the level of central sensitization correlated with the level of non-crisis pain. However, in patients who were taking long-term opioid therapy and also had higher levels of central sensitization and clinical pain, the correlation essentially vanished.

Dr Carroll said this was surprising and suggests the mechanisms of pain in SCD patients on long-term opioid therapy may be different from patients who don’t take daily opioids for pain.

Dr Carroll cautioned that this work is preliminary and should not lead to the discontinuation of long-term opioid therapy in SCD patients.

“We need to better understand how long-term opioid use affects pain sensitization and determine if certain people are more sensitive to these effects so we can prescribe the best treatment option for each individual patient,” Dr Carroll said. “We also need to learn more about how sickle cell disease may sensitize the nervous system.”

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Pregnant woman
Photo by Nina Matthews

A blood test developed to diagnose a rare genetic blood cell disorder, atypical hemolytic uremic syndrome (aHUS), may also aid in the diagnosis of HELLP syndrome, a life-threatening high blood pressure condition that affects 1% of all pregnant women.

The study, based on blood samples from a small number of women, suggests that aHUS has similar underlying biochemistry to HELLP, which affects hemolysis, elevates liver enzymes, and causes a low platelet count. Both conditions have over activation of the alternative pathway of complement.

At present, no diagnostic blood or biomarker test exists to diagnose HELLP, which is thought to be a severe form of preeclampsia. The condition is diagnosed only by its symptoms.

Senior study author Robert Brodsky, MD, of Johns Hopkins, and his team developed the modified Ham test to diagnose aHUS, a genetic disorder in which abnormal blood clots form in small blood vessels in the kidneys. They published that work last year in Blood.
 
The two conditions share a number of traits, such as hemolysis, elevated liver enzymes, a low platelet count, kidney dysfunction, high blood pressure, and seizures. This led the investigators to believe that the modified Ham test could also help identify women with HELLP syndrome.

"The clinical implications from an obstetric point of view are potentially huge," said lead study author Arthur Vaught, MD, also of Johns Hopkins. "If this works, we can reduce pre-term deliveries, stays in the neonatal intensive care unit, and other complications for mothers and their babies."

The team analyzed serum samples from 14 women with classic or atypical HELLP syndrome, 7 with severe preeclampsia, 11 women with normal pregnancies, and 8 healthy nonpregnant women. All pregnant women were at least 23 weeks’ gestation, the point at which HELLP symptoms start to arise.

The team evaluated patient sera using terminal product of complement activation (C5b-9). They observed that women with classic or atypical HELLP had increased complement activation compared to nonpregnant controls.

Women with classic HELLP had an average cell killing of 34.3% compared with 26% in women with atypical HELLP, 5% in women with normal pregnancies, and3.3% in women who were not pregnant.

The investigators then added eculizumab to HELLP sera to see whether the agent could inhibit complement activation. They found that mixing HELLP serum with eculizumab-containing serum significantly decreased cell killing compared with HELLP serum alone.

The kill rate in women with classic or atypical HELLP decreased from 34% to 5% with eculizumab.

Eculizumab (Soliris), manufactured by Alexion Pharmaceuticals, is a monoclonal antibody approved by the US Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and aHUS.

Further investigation is required to confirm these findings, but thus far, the investigators believe the modified Ham assay may assist in diagnosing the HELLP syndrome and corroborate its relationship to aHUS.

The current study by Vaught et al is published in Experimental Hematology.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

SAN FRANCISCO—A new study has shown that hydroxyurea (HU) can improve lung function in young patients with sickle cell disease (SCD).

“Persons with sickle cell disease experience an annual decline in lung function that starts in childhood,” said study investigator Anya McLaren, MD, of The Hospital for Sick Children in Toronto, Ontario, Canada.

“This study is the first of its kind to look at the effect of hydroxyurea on lung function. We found that hydroxyurea improves annual pulmonary function decline in children with sickle cell disease by more than one-third.”

The study was presented at the ATS 2016 International Conference as abstract 7225.

For this study, Dr McLaren and her colleagues evaluated the effects of HU in 94 SCD patients. The patients’ average age at baseline was 11 (range, 6 to 20), 96% of patients had HbSS genotype, and 47% were male.

The patients were followed for 4 years after HU initiation. The investigators assessed lung function before and after HU initiation in a few ways.

They used the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air can be measured during the first second of the forced breath (FEV1) and at later time points.

Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test. If the FEV1/FVC ratio is less than 80%, it indicates that an obstructive defect is present.

The investigators also assessed FEF25-75, or the forced expiratory flow at 25%–75% of FVC. This measurement helps determine if there is an obstruction in the airway.

In addition, the team measured total lung capacity.

Results

The investigators found no significant change in total lung capacity, FVC, or FEV1/FVC predicted measurements after patients began receiving HU.

However, there were significant improvements in both FEV1 and FEF25-75 after treatment.

The annual rate of decline in predicted FEV1 and FEF25-75 before patients started HU was -1.98%/year (95% CI -2.57 to -1.39) and -3.59%/year (95% CI -4.43 to -2.75), respectively.

After HU treatment began, there was a significant (P<0.05) improvement in the annual decline, to -1.28%/year (95% CI -1.79 to -0.76) and -2.88%/year (95% CI -3.49 to -2.28), respectively.

The investigators noted that changes in FEV1 and FEF25-75 were independent of a patient’s age at baseline and the time from HU therapy initiation.

Dr McLaren pointed out that HU is underused in SCD patients, likely because clinicians are concerned about patient non-compliance and afraid of potential side effects, particularly carcinogenesis. But some of those fears may be unfounded, she said.

“Long-term observational studies suggest beneficial effects [of HU] without excessive damage to bone marrow, deleterious effects on growth and development, altered fertility, accumulation of mutations, or increased carcinogenicity,” Dr McLaren said.

“Evidence that lung function may be better preserved while on hydroxyurea may encourage compliance and adherence to this medication for patients with sickle cell disease. In combination with the established safety data, it hopefully will promote physician recommendations for hydroxyurea initiation and encouragement of compliance.”

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

SAN FRANCISCO—A new study has shown that hydroxyurea (HU) can improve lung function in young patients with sickle cell disease (SCD).

“Persons with sickle cell disease experience an annual decline in lung function that starts in childhood,” said study investigator Anya McLaren, MD, of The Hospital for Sick Children in Toronto, Ontario, Canada.

“This study is the first of its kind to look at the effect of hydroxyurea on lung function. We found that hydroxyurea improves annual pulmonary function decline in children with sickle cell disease by more than one-third.”

The study was presented at the ATS 2016 International Conference as abstract 7225.

For this study, Dr McLaren and her colleagues evaluated the effects of HU in 94 SCD patients. The patients’ average age at baseline was 11 (range, 6 to 20), 96% of patients had HbSS genotype, and 47% were male.

The patients were followed for 4 years after HU initiation. The investigators assessed lung function before and after HU initiation in a few ways.

They used the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air can be measured during the first second of the forced breath (FEV1) and at later time points.

Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test. If the FEV1/FVC ratio is less than 80%, it indicates that an obstructive defect is present.

The investigators also assessed FEF25-75, or the forced expiratory flow at 25%–75% of FVC. This measurement helps determine if there is an obstruction in the airway.

In addition, the team measured total lung capacity.

Results

The investigators found no significant change in total lung capacity, FVC, or FEV1/FVC predicted measurements after patients began receiving HU.

However, there were significant improvements in both FEV1 and FEF25-75 after treatment.

The annual rate of decline in predicted FEV1 and FEF25-75 before patients started HU was -1.98%/year (95% CI -2.57 to -1.39) and -3.59%/year (95% CI -4.43 to -2.75), respectively.

After HU treatment began, there was a significant (P<0.05) improvement in the annual decline, to -1.28%/year (95% CI -1.79 to -0.76) and -2.88%/year (95% CI -3.49 to -2.28), respectively.

The investigators noted that changes in FEV1 and FEF25-75 were independent of a patient’s age at baseline and the time from HU therapy initiation.

Dr McLaren pointed out that HU is underused in SCD patients, likely because clinicians are concerned about patient non-compliance and afraid of potential side effects, particularly carcinogenesis. But some of those fears may be unfounded, she said.

“Long-term observational studies suggest beneficial effects [of HU] without excessive damage to bone marrow, deleterious effects on growth and development, altered fertility, accumulation of mutations, or increased carcinogenicity,” Dr McLaren said.

“Evidence that lung function may be better preserved while on hydroxyurea may encourage compliance and adherence to this medication for patients with sickle cell disease. In combination with the established safety data, it hopefully will promote physician recommendations for hydroxyurea initiation and encouragement of compliance.”

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

SAN FRANCISCO—A new study has shown that hydroxyurea (HU) can improve lung function in young patients with sickle cell disease (SCD).

“Persons with sickle cell disease experience an annual decline in lung function that starts in childhood,” said study investigator Anya McLaren, MD, of The Hospital for Sick Children in Toronto, Ontario, Canada.

“This study is the first of its kind to look at the effect of hydroxyurea on lung function. We found that hydroxyurea improves annual pulmonary function decline in children with sickle cell disease by more than one-third.”

The study was presented at the ATS 2016 International Conference as abstract 7225.

For this study, Dr McLaren and her colleagues evaluated the effects of HU in 94 SCD patients. The patients’ average age at baseline was 11 (range, 6 to 20), 96% of patients had HbSS genotype, and 47% were male.

The patients were followed for 4 years after HU initiation. The investigators assessed lung function before and after HU initiation in a few ways.

They used the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air can be measured during the first second of the forced breath (FEV1) and at later time points.

Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test. If the FEV1/FVC ratio is less than 80%, it indicates that an obstructive defect is present.

The investigators also assessed FEF25-75, or the forced expiratory flow at 25%–75% of FVC. This measurement helps determine if there is an obstruction in the airway.

In addition, the team measured total lung capacity.

Results

The investigators found no significant change in total lung capacity, FVC, or FEV1/FVC predicted measurements after patients began receiving HU.

However, there were significant improvements in both FEV1 and FEF25-75 after treatment.

The annual rate of decline in predicted FEV1 and FEF25-75 before patients started HU was -1.98%/year (95% CI -2.57 to -1.39) and -3.59%/year (95% CI -4.43 to -2.75), respectively.

After HU treatment began, there was a significant (P<0.05) improvement in the annual decline, to -1.28%/year (95% CI -1.79 to -0.76) and -2.88%/year (95% CI -3.49 to -2.28), respectively.

The investigators noted that changes in FEV1 and FEF25-75 were independent of a patient’s age at baseline and the time from HU therapy initiation.

Dr McLaren pointed out that HU is underused in SCD patients, likely because clinicians are concerned about patient non-compliance and afraid of potential side effects, particularly carcinogenesis. But some of those fears may be unfounded, she said.

“Long-term observational studies suggest beneficial effects [of HU] without excessive damage to bone marrow, deleterious effects on growth and development, altered fertility, accumulation of mutations, or increased carcinogenicity,” Dr McLaren said.

“Evidence that lung function may be better preserved while on hydroxyurea may encourage compliance and adherence to this medication for patients with sickle cell disease. In combination with the established safety data, it hopefully will promote physician recommendations for hydroxyurea initiation and encouragement of compliance.”

Micrograph showing MDS

The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.

Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.

This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.

However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.

Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.

Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.

To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).

The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.

This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.

The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.

The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.

Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.

The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.

The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.

Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.

Micrograph showing MDS

The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.

Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.

This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.

However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.

Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.

Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.

To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).

The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.

This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.

The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.

The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.

Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.

The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.

The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.

Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.

Micrograph showing MDS

The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.

Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.

This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.

However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.

Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.

Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.

To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).

The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.

This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.

The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.

The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.

Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.

The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.

The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.

Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.

Lab mouse

Preclinical research suggests synthetic peptides called minihepcidins could potentially treat beta-thalassemia and polycythemia vera (PV).

Investigators found that minihepcidin helped to restore normal levels of red blood cells (RBCs) and reduced spleen enlargement in mouse models of beta-thalassemia and PV.

Minihepcidin also controlled the accumulation of excess iron in the mice.

“It seems counterintuitive that one compound could treat two diseases that are quite different, but by restricting iron absorption, it also helps to normalize red blood cell levels in animals,” said study author Stefano Rivella, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“If these preclinical results translate to humans, this could represent a new treatment for both disorders.”

Dr Rivella and his colleagues described the results in Blood.

The investigators used minihepcidins, modified versions of the naturally occurring hormone hepcidin, which regulates iron. Minihepcidins are smaller than the full-length hormone but have long-term stability and long-lasting biological activity when administered to animals.

Previous research showed that minihepcidin treatment can prevent iron overload in mouse models of hemochromatosis.

So Dr Rivella and his colleagues wanted to determine how minihepcidins affect beta-thalassemia and PV in mice separately engineered to model each disease.

The team found that, in young mice that modelled beta-thalassemia, minihepcidin treatment normalized RBC levels and relieved both anemia and iron overload.

In older mice, minihepcidin improved RBC production and did not interfere with a chelating drug used to remove excess iron deposits.

In mice expressing the orthologous JAK2 mutation causing human PV, minihepcidin normalized RBC production.

Because increased iron absorption in PV keeps RBC production in overdrive, when minihepcidin curtailed iron absorption, it lowered the abnormally high numbers of RBCs, which also reduced spleen enlargement.

Dr Rivella noted that if minihepcidins prove successful in clinical trials, they may provide an important tool in treating these blood disorders.

“In animals affected by beta-thalassemia, the compound blocks iron from getting into organs but doesn’t remove excess iron already in organs and tissues,” Dr Rivella said. “If minihepcidins are used in older patients, they would need to be combined with existing chelating drugs that remove the already-accumulated iron.”

However, he added that, in beta-thalassemia, providing minihepcidins in childhood might halt iron accumulation and prevent more severe adult disease.

In PV, minihepcidins may help normalize a patient’s RBC production but, as in beta-thalassemia, would not treat the underlying disease-causing mutations.

Merganser Biotech Inc. is developing minihepcidins as novel therapies for rare hematologic diseases. Merganser’s lead compound, M012, is now under evaluation in a phase 1 clinical program as a potential therapy for beta-thalassemia, low-risk myelodysplasia, PV, alpha-thalassemia, and sickle cell disease.

The company’s chief executive officer, Brian MacDonald, MB ChB, PhD, is a co-author of the current study. Dr Rivella is a paid consultant on Merganser Biotech’s clinical trial, owns restricted stocks in Merganser, and is a member of its scientific advisory board.

Lab mouse

Preclinical research suggests synthetic peptides called minihepcidins could potentially treat beta-thalassemia and polycythemia vera (PV).

Investigators found that minihepcidin helped to restore normal levels of red blood cells (RBCs) and reduced spleen enlargement in mouse models of beta-thalassemia and PV.

Minihepcidin also controlled the accumulation of excess iron in the mice.

“It seems counterintuitive that one compound could treat two diseases that are quite different, but by restricting iron absorption, it also helps to normalize red blood cell levels in animals,” said study author Stefano Rivella, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“If these preclinical results translate to humans, this could represent a new treatment for both disorders.”

Dr Rivella and his colleagues described the results in Blood.

The investigators used minihepcidins, modified versions of the naturally occurring hormone hepcidin, which regulates iron. Minihepcidins are smaller than the full-length hormone but have long-term stability and long-lasting biological activity when administered to animals.

Previous research showed that minihepcidin treatment can prevent iron overload in mouse models of hemochromatosis.

So Dr Rivella and his colleagues wanted to determine how minihepcidins affect beta-thalassemia and PV in mice separately engineered to model each disease.

The team found that, in young mice that modelled beta-thalassemia, minihepcidin treatment normalized RBC levels and relieved both anemia and iron overload.

In older mice, minihepcidin improved RBC production and did not interfere with a chelating drug used to remove excess iron deposits.

In mice expressing the orthologous JAK2 mutation causing human PV, minihepcidin normalized RBC production.

Because increased iron absorption in PV keeps RBC production in overdrive, when minihepcidin curtailed iron absorption, it lowered the abnormally high numbers of RBCs, which also reduced spleen enlargement.

Dr Rivella noted that if minihepcidins prove successful in clinical trials, they may provide an important tool in treating these blood disorders.

“In animals affected by beta-thalassemia, the compound blocks iron from getting into organs but doesn’t remove excess iron already in organs and tissues,” Dr Rivella said. “If minihepcidins are used in older patients, they would need to be combined with existing chelating drugs that remove the already-accumulated iron.”

However, he added that, in beta-thalassemia, providing minihepcidins in childhood might halt iron accumulation and prevent more severe adult disease.

In PV, minihepcidins may help normalize a patient’s RBC production but, as in beta-thalassemia, would not treat the underlying disease-causing mutations.

Merganser Biotech Inc. is developing minihepcidins as novel therapies for rare hematologic diseases. Merganser’s lead compound, M012, is now under evaluation in a phase 1 clinical program as a potential therapy for beta-thalassemia, low-risk myelodysplasia, PV, alpha-thalassemia, and sickle cell disease.

The company’s chief executive officer, Brian MacDonald, MB ChB, PhD, is a co-author of the current study. Dr Rivella is a paid consultant on Merganser Biotech’s clinical trial, owns restricted stocks in Merganser, and is a member of its scientific advisory board.

Lab mouse

Preclinical research suggests synthetic peptides called minihepcidins could potentially treat beta-thalassemia and polycythemia vera (PV).

Investigators found that minihepcidin helped to restore normal levels of red blood cells (RBCs) and reduced spleen enlargement in mouse models of beta-thalassemia and PV.

Minihepcidin also controlled the accumulation of excess iron in the mice.

“It seems counterintuitive that one compound could treat two diseases that are quite different, but by restricting iron absorption, it also helps to normalize red blood cell levels in animals,” said study author Stefano Rivella, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“If these preclinical results translate to humans, this could represent a new treatment for both disorders.”

Dr Rivella and his colleagues described the results in Blood.

The investigators used minihepcidins, modified versions of the naturally occurring hormone hepcidin, which regulates iron. Minihepcidins are smaller than the full-length hormone but have long-term stability and long-lasting biological activity when administered to animals.

Previous research showed that minihepcidin treatment can prevent iron overload in mouse models of hemochromatosis.

So Dr Rivella and his colleagues wanted to determine how minihepcidins affect beta-thalassemia and PV in mice separately engineered to model each disease.

The team found that, in young mice that modelled beta-thalassemia, minihepcidin treatment normalized RBC levels and relieved both anemia and iron overload.

In older mice, minihepcidin improved RBC production and did not interfere with a chelating drug used to remove excess iron deposits.

In mice expressing the orthologous JAK2 mutation causing human PV, minihepcidin normalized RBC production.

Because increased iron absorption in PV keeps RBC production in overdrive, when minihepcidin curtailed iron absorption, it lowered the abnormally high numbers of RBCs, which also reduced spleen enlargement.

Dr Rivella noted that if minihepcidins prove successful in clinical trials, they may provide an important tool in treating these blood disorders.

“In animals affected by beta-thalassemia, the compound blocks iron from getting into organs but doesn’t remove excess iron already in organs and tissues,” Dr Rivella said. “If minihepcidins are used in older patients, they would need to be combined with existing chelating drugs that remove the already-accumulated iron.”

However, he added that, in beta-thalassemia, providing minihepcidins in childhood might halt iron accumulation and prevent more severe adult disease.

In PV, minihepcidins may help normalize a patient’s RBC production but, as in beta-thalassemia, would not treat the underlying disease-causing mutations.

Merganser Biotech Inc. is developing minihepcidins as novel therapies for rare hematologic diseases. Merganser’s lead compound, M012, is now under evaluation in a phase 1 clinical program as a potential therapy for beta-thalassemia, low-risk myelodysplasia, PV, alpha-thalassemia, and sickle cell disease.

The company’s chief executive officer, Brian MacDonald, MB ChB, PhD, is a co-author of the current study. Dr Rivella is a paid consultant on Merganser Biotech’s clinical trial, owns restricted stocks in Merganser, and is a member of its scientific advisory board.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Cells undergoing autophagy

Image by Sarah Pfau

Research published in Cell has revealed a new function of genes in the Fanconi anemia (FA) pathway, and investigators believe this finding could have

implications for the treatment of FA and related disorders.

The team found that FA genes are required for selective autophagy.

In particular, the FANCC gene plays a key role in 2 types of selective autophagy: virophagy (the removal of viruses inside the cell) and mitophagy (the removal of mitochondria).

Experiments in mice showed that genetic deletion of FANCC blocks virophagy and increases the animals’ susceptibility to lethal viral encephalitis.

The investigators also found that FANCC protein is required for the clearance of damaged mitochondria and decreases the production of mitochondrial reactive oxygen species and inflammasome activation.

And other genes in the FA pathway are required for mitophagy as well—FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2.

“There’s increasing evidence that the failure of cells to appropriately clear damaged mitochondria leads to abnormal activation of the inflammasome—a process that is emerging as an important contributor to many different diseases,” said study author Beth Levine, MD, of UT Southwestern Medical Center in Dallas, Texas.

“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes.”

FA pathway genes were already known to play a role in DNA repair. The investigators said this new link to autophagy opens up unexplored horizons for understanding the function of these genes in human health and disease.

“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA and to cancers in patients with mutations in FA genes,” said study author Rhea Sumpter, MD, PhD, of UT Southwestern Medical Center.

“We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”

In addition, the autophagy function may partly explain why patients with FA are highly susceptible to infection and cancer, Dr Levine said.

While further research is needed to understand how these findings may be used to treat disease, the investigators said they have identified a novel avenue for developing potential therapies for FA and cancer patients.

“I believe the clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1β), a pro-inflammatory cytokine,” Dr Sumpter said.

“Clinically, IL-1β signaling has been targeted with FDA-approved drugs very successfully in several auto-inflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”

Cells undergoing autophagy

Image by Sarah Pfau

Research published in Cell has revealed a new function of genes in the Fanconi anemia (FA) pathway, and investigators believe this finding could have

implications for the treatment of FA and related disorders.

The team found that FA genes are required for selective autophagy.

In particular, the FANCC gene plays a key role in 2 types of selective autophagy: virophagy (the removal of viruses inside the cell) and mitophagy (the removal of mitochondria).

Experiments in mice showed that genetic deletion of FANCC blocks virophagy and increases the animals’ susceptibility to lethal viral encephalitis.

The investigators also found that FANCC protein is required for the clearance of damaged mitochondria and decreases the production of mitochondrial reactive oxygen species and inflammasome activation.

And other genes in the FA pathway are required for mitophagy as well—FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2.

“There’s increasing evidence that the failure of cells to appropriately clear damaged mitochondria leads to abnormal activation of the inflammasome—a process that is emerging as an important contributor to many different diseases,” said study author Beth Levine, MD, of UT Southwestern Medical Center in Dallas, Texas.

“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes.”

FA pathway genes were already known to play a role in DNA repair. The investigators said this new link to autophagy opens up unexplored horizons for understanding the function of these genes in human health and disease.

“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA and to cancers in patients with mutations in FA genes,” said study author Rhea Sumpter, MD, PhD, of UT Southwestern Medical Center.

“We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”

In addition, the autophagy function may partly explain why patients with FA are highly susceptible to infection and cancer, Dr Levine said.

While further research is needed to understand how these findings may be used to treat disease, the investigators said they have identified a novel avenue for developing potential therapies for FA and cancer patients.

“I believe the clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1β), a pro-inflammatory cytokine,” Dr Sumpter said.

“Clinically, IL-1β signaling has been targeted with FDA-approved drugs very successfully in several auto-inflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”

Cells undergoing autophagy

Image by Sarah Pfau

Research published in Cell has revealed a new function of genes in the Fanconi anemia (FA) pathway, and investigators believe this finding could have

implications for the treatment of FA and related disorders.

The team found that FA genes are required for selective autophagy.

In particular, the FANCC gene plays a key role in 2 types of selective autophagy: virophagy (the removal of viruses inside the cell) and mitophagy (the removal of mitochondria).

Experiments in mice showed that genetic deletion of FANCC blocks virophagy and increases the animals’ susceptibility to lethal viral encephalitis.

The investigators also found that FANCC protein is required for the clearance of damaged mitochondria and decreases the production of mitochondrial reactive oxygen species and inflammasome activation.

And other genes in the FA pathway are required for mitophagy as well—FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2.

“There’s increasing evidence that the failure of cells to appropriately clear damaged mitochondria leads to abnormal activation of the inflammasome—a process that is emerging as an important contributor to many different diseases,” said study author Beth Levine, MD, of UT Southwestern Medical Center in Dallas, Texas.

“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes.”

FA pathway genes were already known to play a role in DNA repair. The investigators said this new link to autophagy opens up unexplored horizons for understanding the function of these genes in human health and disease.

“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA and to cancers in patients with mutations in FA genes,” said study author Rhea Sumpter, MD, PhD, of UT Southwestern Medical Center.

“We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”

In addition, the autophagy function may partly explain why patients with FA are highly susceptible to infection and cancer, Dr Levine said.

While further research is needed to understand how these findings may be used to treat disease, the investigators said they have identified a novel avenue for developing potential therapies for FA and cancer patients.

“I believe the clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1β), a pro-inflammatory cytokine,” Dr Sumpter said.

“Clinically, IL-1β signaling has been targeted with FDA-approved drugs very successfully in several auto-inflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”