Anemia

HSCT preparation

Photo by Chad McNeeley

A retrospective study suggests that, for patients with hematologic disorders, a haploidentical hematopoietic stem cell transplant (HSCT)

can be roughly as safe and effective as a fully matched HSCT.

The study showed that, when patients received an identical conditioning regimen, graft T-cell dose, and graft-vs-host disease (GVHD) prophylaxis, haploidentical and fully matched HSCTs produced comparable results.

Patients had similar rates of overall and progression-free survival, relapse, non-relapse mortality, and chronic GVHD.

However, patients who received haploidentical transplants had higher rates of grade 2-4 acute GVHD and cytomegalovirus reactivation.

Researchers reported these results in Biology of Blood and Marrow Transplantation.

“This is the first study to compare the gold standard to a half-match using an identical protocol,” said Neal Flomenberg, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

“The field has debated whether the differences in outcomes between full and partial matches were caused by the quality of the match or by all the procedures the patient goes through before and after the donor cells are administered. We haven’t had a clear answer.”

With that in mind, Dr Flomenberg and his colleagues compared 3-year outcome data from patients who received haploidentical HSCTs (n=50) or fully matched HSCTs (n=27), when both groups of patients were treated with a 2-step protocol.

The patients had acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=20), myelodysplastic syndromes/myeloproliferative neoplasms (n=7), non-Hodgkin lymphoma (n=11), and aplastic anemia (n=1).

The 2-step protocol

All patients received a myeloablative conditioning regimen consisting of 12 Gy of total body irradiation administered in 8 fractions over 4 days. After the last fraction, they received a fixed T-cell dose (2 x 10⁸ cells/kg), which was followed, 2 days later, by cyclophosphamide at 60 mg/kg/day for 2 days.

Twenty-four hours after they completed cyclophosphamide, patients received CD34-selected peripheral blood stem cells from a half-matched or fully matched donor.

On day -1, patients began taking tacrolimus and mycophenolate mofetil as GVHD prophylaxis. They also received growth factor support (granulocyte-macrophage colony-stimulating factor at 250 μg/m²) starting on day +1.

In the absence of GVHD, mycophenolate mofetil was discontinued on day 28 and tacrolimus was tapered, starting on day +60 after HSCT.

Results

The researchers said that early immune recovery was comparable between the patient groups in nearly all assessed T-cell subsets. The exception was the median CD3/CD8 cell count, which was significantly higher at day 28 in the fully matched group than the haploidentical group (P=0.029).

Survival rates were comparable between the groups. The estimated 3-year overall survival was 70% in the haploidentical group and 71% in the fully matched group (P=0.81). The 3-year progression-free survival was 68% and 70%, respectively (P=0.97).

The 3-year cumulative incidence of non-relapse mortality was 10% in the haploidentical group and 4% in the fully matched group (P=0.34). The 3-year cumulative incidence of relapse was 21% and 27%, respectively (P=0.93).

The 100-day cumulative incidence of grade 2-4 acute GVHD was significantly higher in the haploidentical group than the fully matched group—40% and 8%, respectively (P<0.001).  But there was no significant difference in the incidence of grade 3-4 acute GVHD—6% and 4%, respectively (P=0.49).

The cumulative incidence of chronic GVHD at 2 years was not significantly different between the haploidentical and fully matched groups—19% and 12%, respectively (P=0.47). The same was true for severe chronic GVHD—4% and 8%, respectively (P=0.49).

The cumulative incidence of cytomegalovirus reactivation was significantly higher in the haploidentical group than the fully matched group—68% and 19%, respectively (P<0.001).

There were no deaths from infections or GVHD in either group.

“The results of the current study are certainly encouraging and suggest that outcomes from a half-matched, related donor are similar to fully matched donors,” said study author Sameh Gaballa, MD, also of Thomas Jefferson University.

“It might be time to reassess whether half-matched, related transplants can be considered the best alternative donor source for patients lacking a fully matched family member donor. For that, we’ll need more evidence from a randomly controlled, prospective trial, rather than studies that look at patient data retrospectively, to help solidify our findings here.”

HSCT preparation

Photo by Chad McNeeley

A retrospective study suggests that, for patients with hematologic disorders, a haploidentical hematopoietic stem cell transplant (HSCT)

can be roughly as safe and effective as a fully matched HSCT.

The study showed that, when patients received an identical conditioning regimen, graft T-cell dose, and graft-vs-host disease (GVHD) prophylaxis, haploidentical and fully matched HSCTs produced comparable results.

Patients had similar rates of overall and progression-free survival, relapse, non-relapse mortality, and chronic GVHD.

However, patients who received haploidentical transplants had higher rates of grade 2-4 acute GVHD and cytomegalovirus reactivation.

Researchers reported these results in Biology of Blood and Marrow Transplantation.

“This is the first study to compare the gold standard to a half-match using an identical protocol,” said Neal Flomenberg, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

“The field has debated whether the differences in outcomes between full and partial matches were caused by the quality of the match or by all the procedures the patient goes through before and after the donor cells are administered. We haven’t had a clear answer.”

With that in mind, Dr Flomenberg and his colleagues compared 3-year outcome data from patients who received haploidentical HSCTs (n=50) or fully matched HSCTs (n=27), when both groups of patients were treated with a 2-step protocol.

The patients had acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=20), myelodysplastic syndromes/myeloproliferative neoplasms (n=7), non-Hodgkin lymphoma (n=11), and aplastic anemia (n=1).

The 2-step protocol

All patients received a myeloablative conditioning regimen consisting of 12 Gy of total body irradiation administered in 8 fractions over 4 days. After the last fraction, they received a fixed T-cell dose (2 x 10⁸ cells/kg), which was followed, 2 days later, by cyclophosphamide at 60 mg/kg/day for 2 days.

Twenty-four hours after they completed cyclophosphamide, patients received CD34-selected peripheral blood stem cells from a half-matched or fully matched donor.

On day -1, patients began taking tacrolimus and mycophenolate mofetil as GVHD prophylaxis. They also received growth factor support (granulocyte-macrophage colony-stimulating factor at 250 μg/m²) starting on day +1.

In the absence of GVHD, mycophenolate mofetil was discontinued on day 28 and tacrolimus was tapered, starting on day +60 after HSCT.

Results

The researchers said that early immune recovery was comparable between the patient groups in nearly all assessed T-cell subsets. The exception was the median CD3/CD8 cell count, which was significantly higher at day 28 in the fully matched group than the haploidentical group (P=0.029).

Survival rates were comparable between the groups. The estimated 3-year overall survival was 70% in the haploidentical group and 71% in the fully matched group (P=0.81). The 3-year progression-free survival was 68% and 70%, respectively (P=0.97).

The 3-year cumulative incidence of non-relapse mortality was 10% in the haploidentical group and 4% in the fully matched group (P=0.34). The 3-year cumulative incidence of relapse was 21% and 27%, respectively (P=0.93).

The 100-day cumulative incidence of grade 2-4 acute GVHD was significantly higher in the haploidentical group than the fully matched group—40% and 8%, respectively (P<0.001).  But there was no significant difference in the incidence of grade 3-4 acute GVHD—6% and 4%, respectively (P=0.49).

The cumulative incidence of chronic GVHD at 2 years was not significantly different between the haploidentical and fully matched groups—19% and 12%, respectively (P=0.47). The same was true for severe chronic GVHD—4% and 8%, respectively (P=0.49).

The cumulative incidence of cytomegalovirus reactivation was significantly higher in the haploidentical group than the fully matched group—68% and 19%, respectively (P<0.001).

There were no deaths from infections or GVHD in either group.

“The results of the current study are certainly encouraging and suggest that outcomes from a half-matched, related donor are similar to fully matched donors,” said study author Sameh Gaballa, MD, also of Thomas Jefferson University.

“It might be time to reassess whether half-matched, related transplants can be considered the best alternative donor source for patients lacking a fully matched family member donor. For that, we’ll need more evidence from a randomly controlled, prospective trial, rather than studies that look at patient data retrospectively, to help solidify our findings here.”

HSCT preparation

Photo by Chad McNeeley

A retrospective study suggests that, for patients with hematologic disorders, a haploidentical hematopoietic stem cell transplant (HSCT)

can be roughly as safe and effective as a fully matched HSCT.

The study showed that, when patients received an identical conditioning regimen, graft T-cell dose, and graft-vs-host disease (GVHD) prophylaxis, haploidentical and fully matched HSCTs produced comparable results.

Patients had similar rates of overall and progression-free survival, relapse, non-relapse mortality, and chronic GVHD.

However, patients who received haploidentical transplants had higher rates of grade 2-4 acute GVHD and cytomegalovirus reactivation.

Researchers reported these results in Biology of Blood and Marrow Transplantation.

“This is the first study to compare the gold standard to a half-match using an identical protocol,” said Neal Flomenberg, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

“The field has debated whether the differences in outcomes between full and partial matches were caused by the quality of the match or by all the procedures the patient goes through before and after the donor cells are administered. We haven’t had a clear answer.”

With that in mind, Dr Flomenberg and his colleagues compared 3-year outcome data from patients who received haploidentical HSCTs (n=50) or fully matched HSCTs (n=27), when both groups of patients were treated with a 2-step protocol.

The patients had acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=20), myelodysplastic syndromes/myeloproliferative neoplasms (n=7), non-Hodgkin lymphoma (n=11), and aplastic anemia (n=1).

The 2-step protocol

All patients received a myeloablative conditioning regimen consisting of 12 Gy of total body irradiation administered in 8 fractions over 4 days. After the last fraction, they received a fixed T-cell dose (2 x 10⁸ cells/kg), which was followed, 2 days later, by cyclophosphamide at 60 mg/kg/day for 2 days.

Twenty-four hours after they completed cyclophosphamide, patients received CD34-selected peripheral blood stem cells from a half-matched or fully matched donor.

On day -1, patients began taking tacrolimus and mycophenolate mofetil as GVHD prophylaxis. They also received growth factor support (granulocyte-macrophage colony-stimulating factor at 250 μg/m²) starting on day +1.

In the absence of GVHD, mycophenolate mofetil was discontinued on day 28 and tacrolimus was tapered, starting on day +60 after HSCT.

Results

The researchers said that early immune recovery was comparable between the patient groups in nearly all assessed T-cell subsets. The exception was the median CD3/CD8 cell count, which was significantly higher at day 28 in the fully matched group than the haploidentical group (P=0.029).

Survival rates were comparable between the groups. The estimated 3-year overall survival was 70% in the haploidentical group and 71% in the fully matched group (P=0.81). The 3-year progression-free survival was 68% and 70%, respectively (P=0.97).

The 3-year cumulative incidence of non-relapse mortality was 10% in the haploidentical group and 4% in the fully matched group (P=0.34). The 3-year cumulative incidence of relapse was 21% and 27%, respectively (P=0.93).

The 100-day cumulative incidence of grade 2-4 acute GVHD was significantly higher in the haploidentical group than the fully matched group—40% and 8%, respectively (P<0.001).  But there was no significant difference in the incidence of grade 3-4 acute GVHD—6% and 4%, respectively (P=0.49).

The cumulative incidence of chronic GVHD at 2 years was not significantly different between the haploidentical and fully matched groups—19% and 12%, respectively (P=0.47). The same was true for severe chronic GVHD—4% and 8%, respectively (P=0.49).

The cumulative incidence of cytomegalovirus reactivation was significantly higher in the haploidentical group than the fully matched group—68% and 19%, respectively (P<0.001).

There were no deaths from infections or GVHD in either group.

“The results of the current study are certainly encouraging and suggest that outcomes from a half-matched, related donor are similar to fully matched donors,” said study author Sameh Gaballa, MD, also of Thomas Jefferson University.

“It might be time to reassess whether half-matched, related transplants can be considered the best alternative donor source for patients lacking a fully matched family member donor. For that, we’ll need more evidence from a randomly controlled, prospective trial, rather than studies that look at patient data retrospectively, to help solidify our findings here.”

Vial of heparin

Researchers believe they have identified a therapeutic target for heparin-induced thrombocytopenia (HIT).

The team noted that HIT is caused by antibodies to complexes that form between platelet factor 4 (PF4), which is released from activated platelets, and heparin or cellular glycosaminoglycans.

The researchers elucidated the crystal structure of 3 PF4 complexes and found evidence suggesting that tetramerization of PF4 is targetable.

Zheng Cai, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Nature Communications.

Previously, the researchers identified KKO, a murine monoclonal antibody to PF4/heparin complexes that causes HIT in a murine model. The team said human HIT antibodies compete with KKO for binding to PF4/heparin, and KKO augments the formation of pathogenic immune complexes.

The researchers also identified RTO, an isotype-matched, anti-PF4 antibody that binds to PF4 but does not generate pathogenic complexes.

For the current study, the team described and compared the crystal structures of PF4 in complex with Fabs derived from KKO and RTO to the structure of PF4 in complex with fondaparinux.

The researchers noted that PF4 molecules can exist singly as monomers, doubly as dimers, and as a 4-part complex called a tetramer, which have an “open” end and a “closed” end.

The crystal structure of PF4 in complex with fondaparinux showed that fondaparinux binds to the “closed” end of the PF4 tetramer, which stabilizes the tetramer.

The crystal structure of PF4 in complex with KKO showed that KKO binds to the “open” end of the stabilized tetramer, making contact with 3 of 4 monomers in the tetramer.

The researchers said this helps explain the requirement for heparin as a backbone for the complex. They also said this finding provides new insight into how a normal host protein such as PF4 can be converted into a target of the host immune system, which leads to an autoimmune disorder.

The crystal structure of PF4 in complex with RTO showed that RTO binds to PF4 monomers rather than tetramers. And RTO binds to the monomers in a way that prevents them from combining into tetramers.

Via cell experiments, the researchers confirmed that RTO prevents the formation of antigenic complexes, as well as the activation of platelets by KKO and human HIT antibodies. RTO also prevented clot formation caused by KKO in a mouse model of HIT.

These results suggest that binding of RTO to PF4 monomers prevents the formation of pathogenic complexes that are central to the pathology of HIT. So the researchers believe RTO can provide the basis for new diagnostics and may pave the way for a therapy to stop HIT early in its progression.

Vial of heparin

Researchers believe they have identified a therapeutic target for heparin-induced thrombocytopenia (HIT).

The team noted that HIT is caused by antibodies to complexes that form between platelet factor 4 (PF4), which is released from activated platelets, and heparin or cellular glycosaminoglycans.

The researchers elucidated the crystal structure of 3 PF4 complexes and found evidence suggesting that tetramerization of PF4 is targetable.

Zheng Cai, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Nature Communications.

Previously, the researchers identified KKO, a murine monoclonal antibody to PF4/heparin complexes that causes HIT in a murine model. The team said human HIT antibodies compete with KKO for binding to PF4/heparin, and KKO augments the formation of pathogenic immune complexes.

The researchers also identified RTO, an isotype-matched, anti-PF4 antibody that binds to PF4 but does not generate pathogenic complexes.

For the current study, the team described and compared the crystal structures of PF4 in complex with Fabs derived from KKO and RTO to the structure of PF4 in complex with fondaparinux.

The researchers noted that PF4 molecules can exist singly as monomers, doubly as dimers, and as a 4-part complex called a tetramer, which have an “open” end and a “closed” end.

The crystal structure of PF4 in complex with fondaparinux showed that fondaparinux binds to the “closed” end of the PF4 tetramer, which stabilizes the tetramer.

The crystal structure of PF4 in complex with KKO showed that KKO binds to the “open” end of the stabilized tetramer, making contact with 3 of 4 monomers in the tetramer.

The researchers said this helps explain the requirement for heparin as a backbone for the complex. They also said this finding provides new insight into how a normal host protein such as PF4 can be converted into a target of the host immune system, which leads to an autoimmune disorder.

The crystal structure of PF4 in complex with RTO showed that RTO binds to PF4 monomers rather than tetramers. And RTO binds to the monomers in a way that prevents them from combining into tetramers.

Via cell experiments, the researchers confirmed that RTO prevents the formation of antigenic complexes, as well as the activation of platelets by KKO and human HIT antibodies. RTO also prevented clot formation caused by KKO in a mouse model of HIT.

These results suggest that binding of RTO to PF4 monomers prevents the formation of pathogenic complexes that are central to the pathology of HIT. So the researchers believe RTO can provide the basis for new diagnostics and may pave the way for a therapy to stop HIT early in its progression.

Vial of heparin

Researchers believe they have identified a therapeutic target for heparin-induced thrombocytopenia (HIT).

The team noted that HIT is caused by antibodies to complexes that form between platelet factor 4 (PF4), which is released from activated platelets, and heparin or cellular glycosaminoglycans.

The researchers elucidated the crystal structure of 3 PF4 complexes and found evidence suggesting that tetramerization of PF4 is targetable.

Zheng Cai, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Nature Communications.

Previously, the researchers identified KKO, a murine monoclonal antibody to PF4/heparin complexes that causes HIT in a murine model. The team said human HIT antibodies compete with KKO for binding to PF4/heparin, and KKO augments the formation of pathogenic immune complexes.

The researchers also identified RTO, an isotype-matched, anti-PF4 antibody that binds to PF4 but does not generate pathogenic complexes.

For the current study, the team described and compared the crystal structures of PF4 in complex with Fabs derived from KKO and RTO to the structure of PF4 in complex with fondaparinux.

The researchers noted that PF4 molecules can exist singly as monomers, doubly as dimers, and as a 4-part complex called a tetramer, which have an “open” end and a “closed” end.

The crystal structure of PF4 in complex with fondaparinux showed that fondaparinux binds to the “closed” end of the PF4 tetramer, which stabilizes the tetramer.

The crystal structure of PF4 in complex with KKO showed that KKO binds to the “open” end of the stabilized tetramer, making contact with 3 of 4 monomers in the tetramer.

The researchers said this helps explain the requirement for heparin as a backbone for the complex. They also said this finding provides new insight into how a normal host protein such as PF4 can be converted into a target of the host immune system, which leads to an autoimmune disorder.

The crystal structure of PF4 in complex with RTO showed that RTO binds to PF4 monomers rather than tetramers. And RTO binds to the monomers in a way that prevents them from combining into tetramers.

Via cell experiments, the researchers confirmed that RTO prevents the formation of antigenic complexes, as well as the activation of platelets by KKO and human HIT antibodies. RTO also prevented clot formation caused by KKO in a mouse model of HIT.

These results suggest that binding of RTO to PF4 monomers prevents the formation of pathogenic complexes that are central to the pathology of HIT. So the researchers believe RTO can provide the basis for new diagnostics and may pave the way for a therapy to stop HIT early in its progression.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Doctor examines child with SCD

Photo courtesy of St. Jude

Children’s Research Hospital

A quality improvement initiative may help reduce the amount of time pediatric patients with sickle cell disease (SCD) wait for pain medication when visiting the emergency department (ED) for a vaso-occlusive episode (VOE).

In a single-center study, the initiative cut patients’ average wait time from triage to the first dose of pain medication by more than 50%—from 56 minutes to 23 minutes.

The researchers described this study in Pediatrics.

The National Heart, Lung, and Blood Institute recommends that a pediatric SCD patient experiencing a VOE be triaged and treated as quickly as possible in the ED. However, previous US studies have indicated that patients often wait, on average, between 65 and 90 minutes for their first dose of pain medication.

“When a child with sickle cell disease comes to the emergency room with pain from a VOE, they likely have been in tremendous pain for hours,” said study author Patricia Kavanagh, MD, of Boston Medical Center (BMC) in Massachusetts.

“The goal of this initiative was to treat the pain episode as quickly and aggressively as possible so that these children could return to their usual activities, including school and time with family and friends.”

Implementing the initiative

From September 2010 to April 2014, a team at BMC implemented the following interventions in the pediatric ED:

1. Using a standardized, time-specific protocol that guides care when the patient is in the ED
2. Using intranasal fentanyl as a first-line pain medication, as placing intravenous lines (IVs) can be difficult in children with SCD
3. Using an online calculator to determine appropriate pain medication doses in line with what is used nationally for children in the ED
4. Providing education on this work to emergency providers and families.

The team implemented these interventions in phases. From September 2010 to May 2011 (baseline), they collected data on the timing of first and subsequent pain medications for children with SCD who presented to the ED with VOEs.

From May to November 2011 (phase 1), the team introduced intranasal fentanyl as the first-line parenteral opioid.

From December 2011 to November 2012 (phase 2), the goal was to streamline VOE care from triage to disposition decision. The team revised the VOE algorithm to recommend 2 doses of intranasal fentanyl, 2 doses of IV opioids, and then a disposition decision. Then, they introduced the pain medication calculator.

From December 2012 to April 2014 (phase 3), the team assessed the sustainability of the interventions from phase 2. The team also revised the VOE algorithm in May 2013 to initiate patient-controlled analgesics after the first dose of IV opioid for patients with severe pain.

Results

The team observed a reduction in the average time from triage to the first dose of a pain medication—either through the nose or IV—from 56 minutes at baseline to 23 minutes in phase 3. The time to the second IV pain medication dose decreased as well—from 106 minutes to 83 minutes.

There was also a reduction in the time it took for the physician to determine whether the patient would be admitted—from 163 minutes to 109 minutes—or discharged—from 271 minutes to 178 minutes.

In addition, patients who were admitted were given patient-controlled analgesics to control their pain, and the time to its initiation decreased from 216 minutes to 141 minutes.

“While future studies are necessary to determine if these results can be replicated at other hospitals, our data indicates that these initiatives could have a tremendous impact on care for kids with SCD across the country,” said James Moses, MD, of BMC.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Preclinical research suggests that usingantibiotics to deplete the body’s microbiome may prevent acute sickle cell crisis in patients with sickle cell disease (SCD) and could potentially offer the first effective strategy for warding off the disease’s long-term complications, such as organ failure.

The work, published in Nature, may also have implications for other inflammatory blood-vessel disorders, including septic shock.

The study was led by Paul Frenette, MD, of Albert Einstein College of Medicine in Bronx, New York. In 2002, Dr Frenette and his colleagues reported that SCD vessel blockages occur when sickled red cells bind to neutrophils that have adhered to the vessel walls.

“This earlier work indicated that not all neutrophils are the same,” Dr Frenette said. “Some appear to be inert, while others appear overly active in promoting inflammation, which is useful for attacking microbes but causes neutrophils to capture sickled red cells inside vessels.”

“So in the current study, we investigated whether the age of the neutrophils might be influencing whether they become active and pro-inflammatory.”

Neutrophils and SCD

The researchers began by transfusing whole blood into mice and then analyzing young neutrophils (harvested 10 minutes post-transfusion) and aged neutrophils (harvested 6 hours post-transfusion). The neutrophils became more active as they aged, suggesting that neutrophils receive external signals telling them to age.

The investigators were able to trace these “aging” signals to the body’s microbiome. They found the microbiome produces chemicals that cross the intestinal barrier and enter the bloodstream, where they generate the aged, overly active subset of neutrophils that contribute to SCD.

“Since the body’s microbiota seem to ‘educate’ neutrophils to age, we realized that purging those microbes through use of antibiotics might help against SCD,” Dr Frenette said.

To find out, he and his colleagues conducted experiments in a mouse model of SCD. These mice possessed 5 times as many aged neutrophils as healthy control mice.

When the researchers depleted the microbiota of SCD mice using antibiotics, they observed a striking reduction in neutrophils but not in other white blood cells (such as monocytes, T cells, and B cells).

Moreover, giving antibiotics to SCD mice appeared to prevent sickle cell crisis. Interactions between neutrophils and red cells were markedly reduced in microbiota-depleted SCD mice, resulting in improved local blood flow and greatly improved survival in the mice.

“What was most surprising and exciting to us was the effect of antibiotics on chronic tissue damage,” Dr Frenette said.

“We found that the spleen enlargement of SCD mice was significantly reduced in the microbiota-depleted animals, and liver analysis revealed major reductions in liver damage, including inflammation, scarring, and tissue death. This is the first time that anything has been found to have an impact on the organ damage that can be so devastating in SCD.”

Septic shock

The investigators then studied septic shock, another serious blood disorder in which activated, pro-inflammatory neutrophils play a role.

To induce septic shock, the team gave control and microbiota-depleted mice a dose of a bacterial toxin that would normally be lethal.

The control mice had the neutrophil aggregates and clumping of neutrophil DNA that contribute to death from septic shock, but the microbiota-depleted mice were largely free of neutrophil complications and survived.

“Remarkably, we could prevent microbiota-depleted mice from surviving septic shock if we infused them with aged neutrophils but not if we infused the same number of young neutrophils,” Dr Frenette said. “So depleting the microbiota may help against inflammatory blood diseases in addition to SCD.”

SCD patient samples

Finally, the researchers investigated whether their findings in mice might be relevant to humans with SCD.

The team obtained blood samples from 9 healthy children and 34 patients with SCD. Eleven patients were taking penicillin daily to ward off infections, as is recommended for children with SCD who are 5 years of age or younger. The other 23 patients with SCD had been off penicillin for at least 2 months.

Consistent with the findings in mice, children with SCD who were not taking penicillin had many more circulating aged neutrophils than the healthy children.

The investigators then compared neutrophil levels in the 2 groups of children with SCD—those taking penicillin and those not on the drug—and found a much lower number of aged neutrophils in the blood of those who were taking penicillin.

“Daily penicillin for patients with SCD younger than 5 works really well in preventing infections,” Dr Frenette said. “Our study suggests that penicillin and other antibiotics could play an even broader role in potentially benefiting older patients.”

“[W]e hope to carry out a clinical trial to determine whether antibiotics can help patients with SCD by preventing the sickle cell crisis and long-term organ damage associated with the disease.”

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Preclinical research suggests that usingantibiotics to deplete the body’s microbiome may prevent acute sickle cell crisis in patients with sickle cell disease (SCD) and could potentially offer the first effective strategy for warding off the disease’s long-term complications, such as organ failure.

The work, published in Nature, may also have implications for other inflammatory blood-vessel disorders, including septic shock.

The study was led by Paul Frenette, MD, of Albert Einstein College of Medicine in Bronx, New York. In 2002, Dr Frenette and his colleagues reported that SCD vessel blockages occur when sickled red cells bind to neutrophils that have adhered to the vessel walls.

“This earlier work indicated that not all neutrophils are the same,” Dr Frenette said. “Some appear to be inert, while others appear overly active in promoting inflammation, which is useful for attacking microbes but causes neutrophils to capture sickled red cells inside vessels.”

“So in the current study, we investigated whether the age of the neutrophils might be influencing whether they become active and pro-inflammatory.”

Neutrophils and SCD

The researchers began by transfusing whole blood into mice and then analyzing young neutrophils (harvested 10 minutes post-transfusion) and aged neutrophils (harvested 6 hours post-transfusion). The neutrophils became more active as they aged, suggesting that neutrophils receive external signals telling them to age.

The investigators were able to trace these “aging” signals to the body’s microbiome. They found the microbiome produces chemicals that cross the intestinal barrier and enter the bloodstream, where they generate the aged, overly active subset of neutrophils that contribute to SCD.

“Since the body’s microbiota seem to ‘educate’ neutrophils to age, we realized that purging those microbes through use of antibiotics might help against SCD,” Dr Frenette said.

To find out, he and his colleagues conducted experiments in a mouse model of SCD. These mice possessed 5 times as many aged neutrophils as healthy control mice.

When the researchers depleted the microbiota of SCD mice using antibiotics, they observed a striking reduction in neutrophils but not in other white blood cells (such as monocytes, T cells, and B cells).

Moreover, giving antibiotics to SCD mice appeared to prevent sickle cell crisis. Interactions between neutrophils and red cells were markedly reduced in microbiota-depleted SCD mice, resulting in improved local blood flow and greatly improved survival in the mice.

“What was most surprising and exciting to us was the effect of antibiotics on chronic tissue damage,” Dr Frenette said.

“We found that the spleen enlargement of SCD mice was significantly reduced in the microbiota-depleted animals, and liver analysis revealed major reductions in liver damage, including inflammation, scarring, and tissue death. This is the first time that anything has been found to have an impact on the organ damage that can be so devastating in SCD.”

Septic shock

The investigators then studied septic shock, another serious blood disorder in which activated, pro-inflammatory neutrophils play a role.

To induce septic shock, the team gave control and microbiota-depleted mice a dose of a bacterial toxin that would normally be lethal.

The control mice had the neutrophil aggregates and clumping of neutrophil DNA that contribute to death from septic shock, but the microbiota-depleted mice were largely free of neutrophil complications and survived.

“Remarkably, we could prevent microbiota-depleted mice from surviving septic shock if we infused them with aged neutrophils but not if we infused the same number of young neutrophils,” Dr Frenette said. “So depleting the microbiota may help against inflammatory blood diseases in addition to SCD.”

SCD patient samples

Finally, the researchers investigated whether their findings in mice might be relevant to humans with SCD.

The team obtained blood samples from 9 healthy children and 34 patients with SCD. Eleven patients were taking penicillin daily to ward off infections, as is recommended for children with SCD who are 5 years of age or younger. The other 23 patients with SCD had been off penicillin for at least 2 months.

Consistent with the findings in mice, children with SCD who were not taking penicillin had many more circulating aged neutrophils than the healthy children.

The investigators then compared neutrophil levels in the 2 groups of children with SCD—those taking penicillin and those not on the drug—and found a much lower number of aged neutrophils in the blood of those who were taking penicillin.

“Daily penicillin for patients with SCD younger than 5 works really well in preventing infections,” Dr Frenette said. “Our study suggests that penicillin and other antibiotics could play an even broader role in potentially benefiting older patients.”

“[W]e hope to carry out a clinical trial to determine whether antibiotics can help patients with SCD by preventing the sickle cell crisis and long-term organ damage associated with the disease.”

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Preclinical research suggests that usingantibiotics to deplete the body’s microbiome may prevent acute sickle cell crisis in patients with sickle cell disease (SCD) and could potentially offer the first effective strategy for warding off the disease’s long-term complications, such as organ failure.

The work, published in Nature, may also have implications for other inflammatory blood-vessel disorders, including septic shock.

The study was led by Paul Frenette, MD, of Albert Einstein College of Medicine in Bronx, New York. In 2002, Dr Frenette and his colleagues reported that SCD vessel blockages occur when sickled red cells bind to neutrophils that have adhered to the vessel walls.

“This earlier work indicated that not all neutrophils are the same,” Dr Frenette said. “Some appear to be inert, while others appear overly active in promoting inflammation, which is useful for attacking microbes but causes neutrophils to capture sickled red cells inside vessels.”

“So in the current study, we investigated whether the age of the neutrophils might be influencing whether they become active and pro-inflammatory.”

Neutrophils and SCD

The researchers began by transfusing whole blood into mice and then analyzing young neutrophils (harvested 10 minutes post-transfusion) and aged neutrophils (harvested 6 hours post-transfusion). The neutrophils became more active as they aged, suggesting that neutrophils receive external signals telling them to age.

The investigators were able to trace these “aging” signals to the body’s microbiome. They found the microbiome produces chemicals that cross the intestinal barrier and enter the bloodstream, where they generate the aged, overly active subset of neutrophils that contribute to SCD.

“Since the body’s microbiota seem to ‘educate’ neutrophils to age, we realized that purging those microbes through use of antibiotics might help against SCD,” Dr Frenette said.

To find out, he and his colleagues conducted experiments in a mouse model of SCD. These mice possessed 5 times as many aged neutrophils as healthy control mice.

When the researchers depleted the microbiota of SCD mice using antibiotics, they observed a striking reduction in neutrophils but not in other white blood cells (such as monocytes, T cells, and B cells).

Moreover, giving antibiotics to SCD mice appeared to prevent sickle cell crisis. Interactions between neutrophils and red cells were markedly reduced in microbiota-depleted SCD mice, resulting in improved local blood flow and greatly improved survival in the mice.

“What was most surprising and exciting to us was the effect of antibiotics on chronic tissue damage,” Dr Frenette said.

“We found that the spleen enlargement of SCD mice was significantly reduced in the microbiota-depleted animals, and liver analysis revealed major reductions in liver damage, including inflammation, scarring, and tissue death. This is the first time that anything has been found to have an impact on the organ damage that can be so devastating in SCD.”

Septic shock

The investigators then studied septic shock, another serious blood disorder in which activated, pro-inflammatory neutrophils play a role.

To induce septic shock, the team gave control and microbiota-depleted mice a dose of a bacterial toxin that would normally be lethal.

The control mice had the neutrophil aggregates and clumping of neutrophil DNA that contribute to death from septic shock, but the microbiota-depleted mice were largely free of neutrophil complications and survived.

“Remarkably, we could prevent microbiota-depleted mice from surviving septic shock if we infused them with aged neutrophils but not if we infused the same number of young neutrophils,” Dr Frenette said. “So depleting the microbiota may help against inflammatory blood diseases in addition to SCD.”

SCD patient samples

Finally, the researchers investigated whether their findings in mice might be relevant to humans with SCD.

The team obtained blood samples from 9 healthy children and 34 patients with SCD. Eleven patients were taking penicillin daily to ward off infections, as is recommended for children with SCD who are 5 years of age or younger. The other 23 patients with SCD had been off penicillin for at least 2 months.

Consistent with the findings in mice, children with SCD who were not taking penicillin had many more circulating aged neutrophils than the healthy children.

The investigators then compared neutrophil levels in the 2 groups of children with SCD—those taking penicillin and those not on the drug—and found a much lower number of aged neutrophils in the blood of those who were taking penicillin.

“Daily penicillin for patients with SCD younger than 5 works really well in preventing infections,” Dr Frenette said. “Our study suggests that penicillin and other antibiotics could play an even broader role in potentially benefiting older patients.”

“[W]e hope to carry out a clinical trial to determine whether antibiotics can help patients with SCD by preventing the sickle cell crisis and long-term organ damage associated with the disease.”

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Eculizumab therapy led to “acceptable” outcomes among pregnant women with paroxysmal nocturnal hemoglobinuria, investigators reported Sept. 9 in the New England Journal of Medicine.

No woman who received eculizumab died while pregnant or within 6 months of delivery; historic mortality rates for these patients are 8%-20%, said Dr. Richard Kelly at St. James’s University Hospital in Leeds, England, and his associates. Treatment with the monoclonal antibody, “has reduced mortality and morbidity associated with PNH and has allowed patients who were previously severely affected to lead a relatively normal life.”

The fetal death rate was 4%, resembling rates of 4%-9% from the era before eculizumab, the researchers said. The rate of premature births also was high (29%) as a result of preeclampsia, suspected intrauterine growth retardation, maternal thrombocytopenia, and slowed fetal movements, they said.

Paroxysmal nocturnal hemoglobinuria is a rare, chronic stem-cell disease in which complement-mediated intravascular hemolysis causes anemia, fatigue, and venous thromboembolism (Adv Exp Med Biol. 2013;735:155-72.). Increased complement activation during pregnancy intensifies the risk of severe hemolytic anemia, fetal morbidity, and fetal mortality for women with PNH. Eculizumab blocks terminal complement activation by binding complement protein C5, and has improved PNH symptoms to the extent that treated women are more likely to consider pregnancy than in the past.

Dr. Kelly and his associates surveyed members of the International PNH Interest Group to study pregnancy outcomes among these women (N Engl J. Med. 2015;373:1032-9). A total of 80% of clinicians responded, reporting data for 75 pregnancies among 61 women, the investigators said. All patients had PNH diagnosed by flow cytometry, and 61% had begun eculizumab therapy before conception. Median age at first pregnancy was 29 years, with a range of 18 to 40 years. The patients received weekly 600-mg IV infusions for 4 weeks, followed by 900 mg every 14 days. Clinicians increased the dose or treatment frequency at their own discretion if patients showed signs of breakthrough intravascular hemolysis.

Two women experienced thrombotic events during treatment, both of which happened soon after delivery. One was a lower-limb deep venous thrombosis, but the other occurred after a patient received a plasma infusion for postpartum hemorrhage. “Plasma contains high levels of complement and can overcome the effects of eculizumab and thereby render the patient susceptible to complications of PNH,” noted the investigators. “The use of plasma should thus be avoided if possible.” Ten samples of breast milk were negative for eculizumab, they added.

Dr. Kelly and 14 of 15 coauthors reported financial relationships outside this work with Alexion Pharmaceuticals, the maker of eculizumab. One coauthor also reported grant support outside this work from Alnylam Pharmaceuticals, Novartis, and Ra Pharma.

Eculizumab therapy led to “acceptable” outcomes among pregnant women with paroxysmal nocturnal hemoglobinuria, investigators reported Sept. 9 in the New England Journal of Medicine.

No woman who received eculizumab died while pregnant or within 6 months of delivery; historic mortality rates for these patients are 8%-20%, said Dr. Richard Kelly at St. James’s University Hospital in Leeds, England, and his associates. Treatment with the monoclonal antibody, “has reduced mortality and morbidity associated with PNH and has allowed patients who were previously severely affected to lead a relatively normal life.”

The fetal death rate was 4%, resembling rates of 4%-9% from the era before eculizumab, the researchers said. The rate of premature births also was high (29%) as a result of preeclampsia, suspected intrauterine growth retardation, maternal thrombocytopenia, and slowed fetal movements, they said.

Paroxysmal nocturnal hemoglobinuria is a rare, chronic stem-cell disease in which complement-mediated intravascular hemolysis causes anemia, fatigue, and venous thromboembolism (Adv Exp Med Biol. 2013;735:155-72.). Increased complement activation during pregnancy intensifies the risk of severe hemolytic anemia, fetal morbidity, and fetal mortality for women with PNH. Eculizumab blocks terminal complement activation by binding complement protein C5, and has improved PNH symptoms to the extent that treated women are more likely to consider pregnancy than in the past.

Dr. Kelly and his associates surveyed members of the International PNH Interest Group to study pregnancy outcomes among these women (N Engl J. Med. 2015;373:1032-9). A total of 80% of clinicians responded, reporting data for 75 pregnancies among 61 women, the investigators said. All patients had PNH diagnosed by flow cytometry, and 61% had begun eculizumab therapy before conception. Median age at first pregnancy was 29 years, with a range of 18 to 40 years. The patients received weekly 600-mg IV infusions for 4 weeks, followed by 900 mg every 14 days. Clinicians increased the dose or treatment frequency at their own discretion if patients showed signs of breakthrough intravascular hemolysis.

Two women experienced thrombotic events during treatment, both of which happened soon after delivery. One was a lower-limb deep venous thrombosis, but the other occurred after a patient received a plasma infusion for postpartum hemorrhage. “Plasma contains high levels of complement and can overcome the effects of eculizumab and thereby render the patient susceptible to complications of PNH,” noted the investigators. “The use of plasma should thus be avoided if possible.” Ten samples of breast milk were negative for eculizumab, they added.

Dr. Kelly and 14 of 15 coauthors reported financial relationships outside this work with Alexion Pharmaceuticals, the maker of eculizumab. One coauthor also reported grant support outside this work from Alnylam Pharmaceuticals, Novartis, and Ra Pharma.

Eculizumab therapy led to “acceptable” outcomes among pregnant women with paroxysmal nocturnal hemoglobinuria, investigators reported Sept. 9 in the New England Journal of Medicine.

No woman who received eculizumab died while pregnant or within 6 months of delivery; historic mortality rates for these patients are 8%-20%, said Dr. Richard Kelly at St. James’s University Hospital in Leeds, England, and his associates. Treatment with the monoclonal antibody, “has reduced mortality and morbidity associated with PNH and has allowed patients who were previously severely affected to lead a relatively normal life.”

The fetal death rate was 4%, resembling rates of 4%-9% from the era before eculizumab, the researchers said. The rate of premature births also was high (29%) as a result of preeclampsia, suspected intrauterine growth retardation, maternal thrombocytopenia, and slowed fetal movements, they said.

Paroxysmal nocturnal hemoglobinuria is a rare, chronic stem-cell disease in which complement-mediated intravascular hemolysis causes anemia, fatigue, and venous thromboembolism (Adv Exp Med Biol. 2013;735:155-72.). Increased complement activation during pregnancy intensifies the risk of severe hemolytic anemia, fetal morbidity, and fetal mortality for women with PNH. Eculizumab blocks terminal complement activation by binding complement protein C5, and has improved PNH symptoms to the extent that treated women are more likely to consider pregnancy than in the past.

Dr. Kelly and his associates surveyed members of the International PNH Interest Group to study pregnancy outcomes among these women (N Engl J. Med. 2015;373:1032-9). A total of 80% of clinicians responded, reporting data for 75 pregnancies among 61 women, the investigators said. All patients had PNH diagnosed by flow cytometry, and 61% had begun eculizumab therapy before conception. Median age at first pregnancy was 29 years, with a range of 18 to 40 years. The patients received weekly 600-mg IV infusions for 4 weeks, followed by 900 mg every 14 days. Clinicians increased the dose or treatment frequency at their own discretion if patients showed signs of breakthrough intravascular hemolysis.

Two women experienced thrombotic events during treatment, both of which happened soon after delivery. One was a lower-limb deep venous thrombosis, but the other occurred after a patient received a plasma infusion for postpartum hemorrhage. “Plasma contains high levels of complement and can overcome the effects of eculizumab and thereby render the patient susceptible to complications of PNH,” noted the investigators. “The use of plasma should thus be avoided if possible.” Ten samples of breast milk were negative for eculizumab, they added.

Dr. Kelly and 14 of 15 coauthors reported financial relationships outside this work with Alexion Pharmaceuticals, the maker of eculizumab. One coauthor also reported grant support outside this work from Alnylam Pharmaceuticals, Novartis, and Ra Pharma.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prefilled syringes of Zarxio

© Sandoz Inc. 2015

The leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to gain approval from the US Food and Drug Administration (FDA), is now available in the US.

Zarxio was approved by the FDA on March 6. The product, made by Sandoz, Inc., is biosimilar to Amgen Inc.’s Neupogen, which was originally licensed in 1991.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

In the US, Zarxio is approved for the same indications as Neupogen. So Zarxio can be prescribed for the following 5 indications.

Patients with cancer receiving myelosuppressive chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy.

Patients with cancer undergoing bone marrow transplant: to reduce the duration of neutropenia and neutropenia-related clinical sequelae—eg, febrile neutropenia—in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant.

Patients undergoing autologous peripheral blood progenitor cell collection and therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia—eg, fever, infections, oropharyngeal ulcers—in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

PIONEER trial

The FDA’s approval of Zarxio was based on data showing that Zarxio is highly similar to Neupogen, with no clinically meaningful differences between the products.

The head-to-head PIONEER study was the final piece of evidence the FDA used to approve Zarxio as biosimilar to Neupogen. Results of the trial were presented at ASH 2014.

Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy—1.17 ± 1.11 and 1.20 ±1.02 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The researchers said there were no obvious differences between Zarxio and Neupogen with regard to treatment-emergent adverse events.

The most common side effects observed with Zarxio are aching bones/muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

For more details on Zarxio, see the full prescribing information or visit www.zarxio.com.

Prefilled syringes of Zarxio

© Sandoz Inc. 2015

The leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to gain approval from the US Food and Drug Administration (FDA), is now available in the US.

Zarxio was approved by the FDA on March 6. The product, made by Sandoz, Inc., is biosimilar to Amgen Inc.’s Neupogen, which was originally licensed in 1991.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

In the US, Zarxio is approved for the same indications as Neupogen. So Zarxio can be prescribed for the following 5 indications.

Patients with cancer receiving myelosuppressive chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy.

Patients with cancer undergoing bone marrow transplant: to reduce the duration of neutropenia and neutropenia-related clinical sequelae—eg, febrile neutropenia—in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant.

Patients undergoing autologous peripheral blood progenitor cell collection and therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia—eg, fever, infections, oropharyngeal ulcers—in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

PIONEER trial

The FDA’s approval of Zarxio was based on data showing that Zarxio is highly similar to Neupogen, with no clinically meaningful differences between the products.

The head-to-head PIONEER study was the final piece of evidence the FDA used to approve Zarxio as biosimilar to Neupogen. Results of the trial were presented at ASH 2014.

Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy—1.17 ± 1.11 and 1.20 ±1.02 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The researchers said there were no obvious differences between Zarxio and Neupogen with regard to treatment-emergent adverse events.

The most common side effects observed with Zarxio are aching bones/muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

For more details on Zarxio, see the full prescribing information or visit www.zarxio.com.

Prefilled syringes of Zarxio

© Sandoz Inc. 2015

The leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to gain approval from the US Food and Drug Administration (FDA), is now available in the US.

Zarxio was approved by the FDA on March 6. The product, made by Sandoz, Inc., is biosimilar to Amgen Inc.’s Neupogen, which was originally licensed in 1991.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

In the US, Zarxio is approved for the same indications as Neupogen. So Zarxio can be prescribed for the following 5 indications.

Patients with cancer receiving myelosuppressive chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy.

Patients with cancer undergoing bone marrow transplant: to reduce the duration of neutropenia and neutropenia-related clinical sequelae—eg, febrile neutropenia—in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant.

Patients undergoing autologous peripheral blood progenitor cell collection and therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with severe chronic neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia—eg, fever, infections, oropharyngeal ulcers—in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

PIONEER trial

The FDA’s approval of Zarxio was based on data showing that Zarxio is highly similar to Neupogen, with no clinically meaningful differences between the products.

The head-to-head PIONEER study was the final piece of evidence the FDA used to approve Zarxio as biosimilar to Neupogen. Results of the trial were presented at ASH 2014.

Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy—1.17 ± 1.11 and 1.20 ±1.02 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The researchers said there were no obvious differences between Zarxio and Neupogen with regard to treatment-emergent adverse events.

The most common side effects observed with Zarxio are aching bones/muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

For more details on Zarxio, see the full prescribing information or visit www.zarxio.com.