Anemia

Daniel Bauer, MD, PhD, a pediatric hematologist and blood disorders researcher in Boston, is one of three finalists for the inaugural Trailblazer Prize for Clinician-Scientists, which is awarded by the Foundation for the National Institutes of Health.

Dr. Bauer, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, was selected based on his research using genome editing to tease out the causes of blood disorders, such as sickle cell disease and beta-thalassemia.

All three finalists for the Trailblazer Prize are early career clinician-scientists whose work has the potential to or has led to innovations in patient care, according to the Foundation for the National Institutes of Health.

The other two finalists are Jaehyuk Choi, MD, PhD, of Northwestern University in Chicago and Michael Fox, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.

Dr. Choi was selected for using genomics to identify mutations in skin cells that can lead to autoinflammatory diseases and cancer. Dr. Fox was selected for the development of innovative techniques to map human brain connectivity that can be used in novel treatments for Parkinson’s disease and depression.

The winner will be announced during a ceremony in Washington on Oct. 24, 2018, and will receive a $10,000 honorarium.

[email protected]

Daniel Bauer, MD, PhD, a pediatric hematologist and blood disorders researcher in Boston, is one of three finalists for the inaugural Trailblazer Prize for Clinician-Scientists, which is awarded by the Foundation for the National Institutes of Health.

Dr. Bauer, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, was selected based on his research using genome editing to tease out the causes of blood disorders, such as sickle cell disease and beta-thalassemia.

All three finalists for the Trailblazer Prize are early career clinician-scientists whose work has the potential to or has led to innovations in patient care, according to the Foundation for the National Institutes of Health.

The other two finalists are Jaehyuk Choi, MD, PhD, of Northwestern University in Chicago and Michael Fox, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.

Dr. Choi was selected for using genomics to identify mutations in skin cells that can lead to autoinflammatory diseases and cancer. Dr. Fox was selected for the development of innovative techniques to map human brain connectivity that can be used in novel treatments for Parkinson’s disease and depression.

The winner will be announced during a ceremony in Washington on Oct. 24, 2018, and will receive a $10,000 honorarium.

[email protected]

Daniel Bauer, MD, PhD, a pediatric hematologist and blood disorders researcher in Boston, is one of three finalists for the inaugural Trailblazer Prize for Clinician-Scientists, which is awarded by the Foundation for the National Institutes of Health.

Dr. Bauer, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, was selected based on his research using genome editing to tease out the causes of blood disorders, such as sickle cell disease and beta-thalassemia.

All three finalists for the Trailblazer Prize are early career clinician-scientists whose work has the potential to or has led to innovations in patient care, according to the Foundation for the National Institutes of Health.

The other two finalists are Jaehyuk Choi, MD, PhD, of Northwestern University in Chicago and Michael Fox, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.

Dr. Choi was selected for using genomics to identify mutations in skin cells that can lead to autoinflammatory diseases and cancer. Dr. Fox was selected for the development of innovative techniques to map human brain connectivity that can be used in novel treatments for Parkinson’s disease and depression.

The winner will be announced during a ceremony in Washington on Oct. 24, 2018, and will receive a $10,000 honorarium.

[email protected]

Red blood cells

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.

With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.

The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.

PNH-301 trial

This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).

Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.

Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.

The study’s co-primary endpoints are:

• Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
• Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.

ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.

ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:

• Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
• Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
• Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
• Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).

Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.

One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.

Switch study

This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.

ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.

Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.

Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:

• The proportion of patients with breakthrough hemolysis
• The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
• The proportion of patients avoiding transfusion
• The proportion of patients with stabilized hemoglobin levels.

ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.

There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.

Red blood cells

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.

With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.

The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.

PNH-301 trial

This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).

Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.

Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.

The study’s co-primary endpoints are:

• Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
• Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.

ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.

ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:

• Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
• Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
• Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
• Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).

Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.

One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.

Switch study

This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.

ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.

Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.

Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:

• The proportion of patients with breakthrough hemolysis
• The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
• The proportion of patients avoiding transfusion
• The proportion of patients with stabilized hemoglobin levels.

ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.

There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.

Red blood cells

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.

With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.

The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.

PNH-301 trial

This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).

Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.

Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.

The study’s co-primary endpoints are:

• Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
• Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.

ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.

ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:

• Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
• Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
• Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
• Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).

Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.

One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.

Switch study

This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.

ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.

Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.

Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:

• The proportion of patients with breakthrough hemolysis
• The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
• The proportion of patients avoiding transfusion
• The proportion of patients with stabilized hemoglobin levels.

ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.

There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.

WASHINGTON – Pediatric patients who received interdisciplinary outpatient care for sickle cell disease–related chronic pain experienced a reduction in average length of stay for pain-related hospitalizations, according to an exploratory analysis of patient outcomes at a single center.

Dr_Microbe/Thinkstock

Experiences at Children’s Mercy Hospital in Kansas City, Mo., have added to the body of evidence supporting integrative care for sickle cell disease (SCD) pain, Derrick L. Goubeaux, DO, said during an interview at the annual symposium of the Foundation for Sickle Cell Disease Research.

With time, chronic pain can become an overlay on pain from vasoocclusive crises as patients with SCD age, shifting the way that patients and providers think about pain, said Dr. Goubeaux, a pediatric hematology/oncology fellow at Children’s Mercy Hospital in Kansas City.

Using a collaborative approach that pulls in psychologists, social workers, and pain management specialists, the hospital’s multidisciplinary Sickle Cell Integrated Pain Program (SCIPP) seeks to optimize pain control by adding nonpharmacologic measures to medications, he said.

Dr. Goubeaux and his colleagues conducted a retrospective chart review that looked at individuals who received care from, or were referred to, the institution’s SCD program. Included in the study were patients who received care for SCD for at least 2 years before their referral to the SCIPP clinic, so that investigators could compare care for those patients before and after SCIPP clinic integration. The study also included patients who had not yet been integrated into SCIPP clinic care, for comparison.

Though the seven patients who were integrated into the SCIPP clinic did not have fewer hospitalizations than the five who were not referred, average length of stay (LOS) for the SCIPP patients dropped from 11 days to 8 days. Mean LOS also decreased for the non-SCIPP patients, from 7.4 to 5.8 days. The number of admissions per month for both groups increased over the study period, from a mean of 0.41 to 0.84 admissions per month for SCIPP patients, and from 0.27 to 0.43 for non-SCIPP patients.

The patients, who ranged in age from 138 to 253 months, mostly had HbSS SCD, but HbSbeta₀, HbSD, and HbSC patients were also included. Four patients in the SCIPP group and two of the non-SCIPP patients were taking hydroxyurea.

Noting that data collection is still in the early stages, Dr. Goubeaux and his collaborators observed that “the LOS has shortened by 3 days in the integrated group, compared to 1.6 days in the [non-SCIPP] group.” They are currently also investigating whether costs per admission and admission-associated opioid use differs for patients integrated into the SCIPP clinic.

Aside from the small number of patients studied, Dr. Goubeaux and his colleagues acknowledged that even non-SCIPP patients are likely to have had pain management and psychology consultations during their inpatient stays – and these consults are conducted by SCIPP-associated providers.

Dr. Goubeaux reported no relevant disclosures or outside sources of funding.

[email protected]

WASHINGTON – Pediatric patients who received interdisciplinary outpatient care for sickle cell disease–related chronic pain experienced a reduction in average length of stay for pain-related hospitalizations, according to an exploratory analysis of patient outcomes at a single center.

Dr_Microbe/Thinkstock

Experiences at Children’s Mercy Hospital in Kansas City, Mo., have added to the body of evidence supporting integrative care for sickle cell disease (SCD) pain, Derrick L. Goubeaux, DO, said during an interview at the annual symposium of the Foundation for Sickle Cell Disease Research.

With time, chronic pain can become an overlay on pain from vasoocclusive crises as patients with SCD age, shifting the way that patients and providers think about pain, said Dr. Goubeaux, a pediatric hematology/oncology fellow at Children’s Mercy Hospital in Kansas City.

Using a collaborative approach that pulls in psychologists, social workers, and pain management specialists, the hospital’s multidisciplinary Sickle Cell Integrated Pain Program (SCIPP) seeks to optimize pain control by adding nonpharmacologic measures to medications, he said.

Dr. Goubeaux and his colleagues conducted a retrospective chart review that looked at individuals who received care from, or were referred to, the institution’s SCD program. Included in the study were patients who received care for SCD for at least 2 years before their referral to the SCIPP clinic, so that investigators could compare care for those patients before and after SCIPP clinic integration. The study also included patients who had not yet been integrated into SCIPP clinic care, for comparison.

Though the seven patients who were integrated into the SCIPP clinic did not have fewer hospitalizations than the five who were not referred, average length of stay (LOS) for the SCIPP patients dropped from 11 days to 8 days. Mean LOS also decreased for the non-SCIPP patients, from 7.4 to 5.8 days. The number of admissions per month for both groups increased over the study period, from a mean of 0.41 to 0.84 admissions per month for SCIPP patients, and from 0.27 to 0.43 for non-SCIPP patients.

The patients, who ranged in age from 138 to 253 months, mostly had HbSS SCD, but HbSbeta₀, HbSD, and HbSC patients were also included. Four patients in the SCIPP group and two of the non-SCIPP patients were taking hydroxyurea.

Noting that data collection is still in the early stages, Dr. Goubeaux and his collaborators observed that “the LOS has shortened by 3 days in the integrated group, compared to 1.6 days in the [non-SCIPP] group.” They are currently also investigating whether costs per admission and admission-associated opioid use differs for patients integrated into the SCIPP clinic.

Aside from the small number of patients studied, Dr. Goubeaux and his colleagues acknowledged that even non-SCIPP patients are likely to have had pain management and psychology consultations during their inpatient stays – and these consults are conducted by SCIPP-associated providers.

Dr. Goubeaux reported no relevant disclosures or outside sources of funding.

[email protected]

WASHINGTON – Pediatric patients who received interdisciplinary outpatient care for sickle cell disease–related chronic pain experienced a reduction in average length of stay for pain-related hospitalizations, according to an exploratory analysis of patient outcomes at a single center.

Dr_Microbe/Thinkstock

Experiences at Children’s Mercy Hospital in Kansas City, Mo., have added to the body of evidence supporting integrative care for sickle cell disease (SCD) pain, Derrick L. Goubeaux, DO, said during an interview at the annual symposium of the Foundation for Sickle Cell Disease Research.

With time, chronic pain can become an overlay on pain from vasoocclusive crises as patients with SCD age, shifting the way that patients and providers think about pain, said Dr. Goubeaux, a pediatric hematology/oncology fellow at Children’s Mercy Hospital in Kansas City.

Using a collaborative approach that pulls in psychologists, social workers, and pain management specialists, the hospital’s multidisciplinary Sickle Cell Integrated Pain Program (SCIPP) seeks to optimize pain control by adding nonpharmacologic measures to medications, he said.

Dr. Goubeaux and his colleagues conducted a retrospective chart review that looked at individuals who received care from, or were referred to, the institution’s SCD program. Included in the study were patients who received care for SCD for at least 2 years before their referral to the SCIPP clinic, so that investigators could compare care for those patients before and after SCIPP clinic integration. The study also included patients who had not yet been integrated into SCIPP clinic care, for comparison.

Though the seven patients who were integrated into the SCIPP clinic did not have fewer hospitalizations than the five who were not referred, average length of stay (LOS) for the SCIPP patients dropped from 11 days to 8 days. Mean LOS also decreased for the non-SCIPP patients, from 7.4 to 5.8 days. The number of admissions per month for both groups increased over the study period, from a mean of 0.41 to 0.84 admissions per month for SCIPP patients, and from 0.27 to 0.43 for non-SCIPP patients.

The patients, who ranged in age from 138 to 253 months, mostly had HbSS SCD, but HbSbeta₀, HbSD, and HbSC patients were also included. Four patients in the SCIPP group and two of the non-SCIPP patients were taking hydroxyurea.

Noting that data collection is still in the early stages, Dr. Goubeaux and his collaborators observed that “the LOS has shortened by 3 days in the integrated group, compared to 1.6 days in the [non-SCIPP] group.” They are currently also investigating whether costs per admission and admission-associated opioid use differs for patients integrated into the SCIPP clinic.

Aside from the small number of patients studied, Dr. Goubeaux and his colleagues acknowledged that even non-SCIPP patients are likely to have had pain management and psychology consultations during their inpatient stays – and these consults are conducted by SCIPP-associated providers.

Dr. Goubeaux reported no relevant disclosures or outside sources of funding.

[email protected]

Micrograph showing MDS

The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503.

The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m².

The agency said additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m² dose level.

One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.

About OXi4503

According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.

This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.

OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

Clinical trials

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.

The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 ASH Annual Meeting.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.

The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503.

The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m².

The agency said additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m² dose level.

One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.

About OXi4503

According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.

This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.

OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

Clinical trials

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.

The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 ASH Annual Meeting.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.

The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503.

The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m².

The agency said additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m² dose level.

One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.

About OXi4503

According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.

This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.

OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

Clinical trials

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.

The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 ASH Annual Meeting.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.

The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Image by Tom Ellenberger

New research suggests the Fanconi anemia (FA) pathway plays a key role in repairing double-strand breaks (DSBs) created by CRISPR-Cas9 genome editing.

Researchers said they found that Cas9-induced single-strand template repair requires the FA pathway, and the protein FANCD2 localizes to Cas9-induced DSBs.

The team said this research provides insight into why CRISPR-Cas9 does not produce equal success in all cells.

Furthermore, the work might help researchers boost the efficiency with which cells insert new DNA into the genome and generally tweak CRISPR-Cas9 editing to get the desired outcome.

“If you want to treat sickle cell anemia, your chances of success are inextricably tied to the efficiency with which you can replace the mutated sickle cell gene with the correct one,” said study author Chris Richardson, PhD, formerly of the University of California, Berkeley, but now at Spotlight Therapeutics in Hayward, California.

“If you harvest a million cells from a patient and you have a 10% insertion rate, that is not as good as if you have 30% to 40%. Being able to manipulate those cells to increase the frequency of this process, called homology-directed repair, is exciting.”

Dr Richardson and his colleagues described this work in Nature Genetics.

CRISPR relies on DNA repair

The researchers noted that CRISPR-Cas9 creates targeted DSBs, and it’s up to the cell to repair the DNA.

This can happen in 2 ways. Enzymes can stitch the dangling ends back together, which often results in one or more bases being added or deleted, disrupting the function of the gene.

Alternatively, other enzymes can patch the break with a single strand of DNA that matches the DNA sequence upstream and downstream of the cut. A complementary DNA strand is created to complete the double-strand repair.

The former method, called non-homologous end-joining, appears to be the most common outcome after CRISPR cutting.

The latter method, homology-directed repair, happens more frequently in some cells than others and requires the presence of DNA that can be used to patch the break. Researchers often supply a single-stranded piece of DNA and hope the cell uses it to replace the faulty sequence with the new one.

Both processes are a bit mysterious, however, and no one knows why some cells readily patch in DNA while others do so infrequently.

“The enthusiasm for using CRISPR-Cas9 for medical or synthetic biology applications is great, but no one really knows what happens after you put it into cells,” Dr Richardson said. “It goes and creates these breaks, and you count on the cells to fix them, but people don’t really understand how that process works.”

To find out which DNA repair enzymes are critical to homology-directed repair after CRISPR cutting, Dr Richardson and his colleagues used a technique called CRISPR interference. They knocked out, one at a time, more than 2000 genes known or suspected to be involved in DNA repair.

The researchers were surprised to find that many of the genes that proved important—homology-directed repair dropped dramatically when they were silenced—were involved in the FA pathway.

FA pathway

The FA pathway was largely understood to repair DNA interstrand crosslinks, where a nucleotide on one strand of DNA bonds tightly with a nucleotide on the adjacent strand, interfering with DNA replication and often killing the cell.

“Based on our work, we believe that the Fanconi anemia pathway plays a major role in fixing other types of lesions as well, but is best understood as the pathway that repairs double-strand breaks,” Dr Richardson said. “After Cas9 editing, the Fanconi anemia pathway is required if you want to insert new DNA.”

The importance of the FA pathway in repairing DSBs casts doubt on some planned CRISPR treatments for Fanconi anemia itself.

Without an active FA pathway, cells may not be able to replace their mutated genes with normal genes after Cas9 makes a cut. In fact, the activity level of the FA pathway may affect how efficiently CRISPR can insert DNA in a specific cell.

The researchers concluded that, while end-joining is the default repair mechanism after a DSB, the FA pathway competes with it, and that higher activity results in more homology-directed repair and less end-joining.

Dr Richardson and his colleagues also found that 1 of the 21 proteins in the FA pathway, FANCD2, always homes in on the site of the DSB created by CRISPR-Cas9. This suggests FANCD2 plays an important role in regulating the insertion of new DNA at the cut site.

The researchers therefore believe FANCD2 could be tweaked to boost the frequency with which a cell inserts DNA via homology-directed repair.

“Also, since FANCD2 localizes to the site of Cas9 breaks, you can use FANCD2 to map where Cas9 is cutting in any cell type,” Dr Richardson said. “If you edit a population of cells and you want to know where the on- and off-target cuts are, you can just map where FANCD2 was found in the genome and you can find the cuts.”

Image by Tom Ellenberger

New research suggests the Fanconi anemia (FA) pathway plays a key role in repairing double-strand breaks (DSBs) created by CRISPR-Cas9 genome editing.

Researchers said they found that Cas9-induced single-strand template repair requires the FA pathway, and the protein FANCD2 localizes to Cas9-induced DSBs.

The team said this research provides insight into why CRISPR-Cas9 does not produce equal success in all cells.

Furthermore, the work might help researchers boost the efficiency with which cells insert new DNA into the genome and generally tweak CRISPR-Cas9 editing to get the desired outcome.

“If you want to treat sickle cell anemia, your chances of success are inextricably tied to the efficiency with which you can replace the mutated sickle cell gene with the correct one,” said study author Chris Richardson, PhD, formerly of the University of California, Berkeley, but now at Spotlight Therapeutics in Hayward, California.

“If you harvest a million cells from a patient and you have a 10% insertion rate, that is not as good as if you have 30% to 40%. Being able to manipulate those cells to increase the frequency of this process, called homology-directed repair, is exciting.”

Dr Richardson and his colleagues described this work in Nature Genetics.

CRISPR relies on DNA repair

The researchers noted that CRISPR-Cas9 creates targeted DSBs, and it’s up to the cell to repair the DNA.

This can happen in 2 ways. Enzymes can stitch the dangling ends back together, which often results in one or more bases being added or deleted, disrupting the function of the gene.

Alternatively, other enzymes can patch the break with a single strand of DNA that matches the DNA sequence upstream and downstream of the cut. A complementary DNA strand is created to complete the double-strand repair.

The former method, called non-homologous end-joining, appears to be the most common outcome after CRISPR cutting.

The latter method, homology-directed repair, happens more frequently in some cells than others and requires the presence of DNA that can be used to patch the break. Researchers often supply a single-stranded piece of DNA and hope the cell uses it to replace the faulty sequence with the new one.

Both processes are a bit mysterious, however, and no one knows why some cells readily patch in DNA while others do so infrequently.

“The enthusiasm for using CRISPR-Cas9 for medical or synthetic biology applications is great, but no one really knows what happens after you put it into cells,” Dr Richardson said. “It goes and creates these breaks, and you count on the cells to fix them, but people don’t really understand how that process works.”

To find out which DNA repair enzymes are critical to homology-directed repair after CRISPR cutting, Dr Richardson and his colleagues used a technique called CRISPR interference. They knocked out, one at a time, more than 2000 genes known or suspected to be involved in DNA repair.

The researchers were surprised to find that many of the genes that proved important—homology-directed repair dropped dramatically when they were silenced—were involved in the FA pathway.

FA pathway

The FA pathway was largely understood to repair DNA interstrand crosslinks, where a nucleotide on one strand of DNA bonds tightly with a nucleotide on the adjacent strand, interfering with DNA replication and often killing the cell.

“Based on our work, we believe that the Fanconi anemia pathway plays a major role in fixing other types of lesions as well, but is best understood as the pathway that repairs double-strand breaks,” Dr Richardson said. “After Cas9 editing, the Fanconi anemia pathway is required if you want to insert new DNA.”

The importance of the FA pathway in repairing DSBs casts doubt on some planned CRISPR treatments for Fanconi anemia itself.

Without an active FA pathway, cells may not be able to replace their mutated genes with normal genes after Cas9 makes a cut. In fact, the activity level of the FA pathway may affect how efficiently CRISPR can insert DNA in a specific cell.

The researchers concluded that, while end-joining is the default repair mechanism after a DSB, the FA pathway competes with it, and that higher activity results in more homology-directed repair and less end-joining.

Dr Richardson and his colleagues also found that 1 of the 21 proteins in the FA pathway, FANCD2, always homes in on the site of the DSB created by CRISPR-Cas9. This suggests FANCD2 plays an important role in regulating the insertion of new DNA at the cut site.

The researchers therefore believe FANCD2 could be tweaked to boost the frequency with which a cell inserts DNA via homology-directed repair.

“Also, since FANCD2 localizes to the site of Cas9 breaks, you can use FANCD2 to map where Cas9 is cutting in any cell type,” Dr Richardson said. “If you edit a population of cells and you want to know where the on- and off-target cuts are, you can just map where FANCD2 was found in the genome and you can find the cuts.”

Image by Tom Ellenberger

New research suggests the Fanconi anemia (FA) pathway plays a key role in repairing double-strand breaks (DSBs) created by CRISPR-Cas9 genome editing.

Researchers said they found that Cas9-induced single-strand template repair requires the FA pathway, and the protein FANCD2 localizes to Cas9-induced DSBs.

The team said this research provides insight into why CRISPR-Cas9 does not produce equal success in all cells.

Furthermore, the work might help researchers boost the efficiency with which cells insert new DNA into the genome and generally tweak CRISPR-Cas9 editing to get the desired outcome.

“If you want to treat sickle cell anemia, your chances of success are inextricably tied to the efficiency with which you can replace the mutated sickle cell gene with the correct one,” said study author Chris Richardson, PhD, formerly of the University of California, Berkeley, but now at Spotlight Therapeutics in Hayward, California.

“If you harvest a million cells from a patient and you have a 10% insertion rate, that is not as good as if you have 30% to 40%. Being able to manipulate those cells to increase the frequency of this process, called homology-directed repair, is exciting.”

Dr Richardson and his colleagues described this work in Nature Genetics.

CRISPR relies on DNA repair

The researchers noted that CRISPR-Cas9 creates targeted DSBs, and it’s up to the cell to repair the DNA.

This can happen in 2 ways. Enzymes can stitch the dangling ends back together, which often results in one or more bases being added or deleted, disrupting the function of the gene.

Alternatively, other enzymes can patch the break with a single strand of DNA that matches the DNA sequence upstream and downstream of the cut. A complementary DNA strand is created to complete the double-strand repair.

The former method, called non-homologous end-joining, appears to be the most common outcome after CRISPR cutting.

The latter method, homology-directed repair, happens more frequently in some cells than others and requires the presence of DNA that can be used to patch the break. Researchers often supply a single-stranded piece of DNA and hope the cell uses it to replace the faulty sequence with the new one.

Both processes are a bit mysterious, however, and no one knows why some cells readily patch in DNA while others do so infrequently.

“The enthusiasm for using CRISPR-Cas9 for medical or synthetic biology applications is great, but no one really knows what happens after you put it into cells,” Dr Richardson said. “It goes and creates these breaks, and you count on the cells to fix them, but people don’t really understand how that process works.”

To find out which DNA repair enzymes are critical to homology-directed repair after CRISPR cutting, Dr Richardson and his colleagues used a technique called CRISPR interference. They knocked out, one at a time, more than 2000 genes known or suspected to be involved in DNA repair.

The researchers were surprised to find that many of the genes that proved important—homology-directed repair dropped dramatically when they were silenced—were involved in the FA pathway.

FA pathway

The FA pathway was largely understood to repair DNA interstrand crosslinks, where a nucleotide on one strand of DNA bonds tightly with a nucleotide on the adjacent strand, interfering with DNA replication and often killing the cell.

“Based on our work, we believe that the Fanconi anemia pathway plays a major role in fixing other types of lesions as well, but is best understood as the pathway that repairs double-strand breaks,” Dr Richardson said. “After Cas9 editing, the Fanconi anemia pathway is required if you want to insert new DNA.”

The importance of the FA pathway in repairing DSBs casts doubt on some planned CRISPR treatments for Fanconi anemia itself.

Without an active FA pathway, cells may not be able to replace their mutated genes with normal genes after Cas9 makes a cut. In fact, the activity level of the FA pathway may affect how efficiently CRISPR can insert DNA in a specific cell.

The researchers concluded that, while end-joining is the default repair mechanism after a DSB, the FA pathway competes with it, and that higher activity results in more homology-directed repair and less end-joining.

Dr Richardson and his colleagues also found that 1 of the 21 proteins in the FA pathway, FANCD2, always homes in on the site of the DSB created by CRISPR-Cas9. This suggests FANCD2 plays an important role in regulating the insertion of new DNA at the cut site.

The researchers therefore believe FANCD2 could be tweaked to boost the frequency with which a cell inserts DNA via homology-directed repair.

“Also, since FANCD2 localizes to the site of Cas9 breaks, you can use FANCD2 to map where Cas9 is cutting in any cell type,” Dr Richardson said. “If you edit a population of cells and you want to know where the on- and off-target cuts are, you can just map where FANCD2 was found in the genome and you can find the cuts.”

Micrograph showing thalassemia

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for Deferiprone Lipomed to treat iron overload in patients with thalassemia major.

Deferiprone Lipomed is a generic version of the iron chelating agent Ferriprox, which has been authorized in the European Union since August 1999.

According to the CHMP, studies have shown that Deferiprone Lipomed is of satisfactory quality and bioequivalent to Ferriprox.

The CHMP’s recommendation for Deferiprone Lipomed will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Deferiprone Lipomed will be available as 500-mg film-coated tablets.

The drug will be authorized for the following uses:

• As monotherapy to treat iron overload in patients with thalassemia major when current chelation therapy is contraindicated or inadequate
• In combination with another chelator in patients with thalassemia major when monotherapy with any iron chelator is ineffective or when prevention or treatment of life-threatening consequences of iron overload justifies rapid or intensive correction.

According to the prescribing information for Ferriprox, the combination of iron chelators should be considered on a case-by-case basis, and patients should be monitored for response and adverse events.

Fatalities and life-threatening situations (caused by agranulocytosis) have been reported with the combination of deferiprone and deferoxamine.

Combination therapy is not recommended when monotherapy with either chelator is adequate or when serum ferritin falls below 500 μg/l. Additionally, there are limited data on the combined use of Ferriprox and deferasirox.

The applicant for Deferiprone Lipomed is Lipomed GmbH.

Micrograph showing thalassemia

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for Deferiprone Lipomed to treat iron overload in patients with thalassemia major.

Deferiprone Lipomed is a generic version of the iron chelating agent Ferriprox, which has been authorized in the European Union since August 1999.

According to the CHMP, studies have shown that Deferiprone Lipomed is of satisfactory quality and bioequivalent to Ferriprox.

The CHMP’s recommendation for Deferiprone Lipomed will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Deferiprone Lipomed will be available as 500-mg film-coated tablets.

The drug will be authorized for the following uses:

• As monotherapy to treat iron overload in patients with thalassemia major when current chelation therapy is contraindicated or inadequate
• In combination with another chelator in patients with thalassemia major when monotherapy with any iron chelator is ineffective or when prevention or treatment of life-threatening consequences of iron overload justifies rapid or intensive correction.

According to the prescribing information for Ferriprox, the combination of iron chelators should be considered on a case-by-case basis, and patients should be monitored for response and adverse events.

Fatalities and life-threatening situations (caused by agranulocytosis) have been reported with the combination of deferiprone and deferoxamine.

Combination therapy is not recommended when monotherapy with either chelator is adequate or when serum ferritin falls below 500 μg/l. Additionally, there are limited data on the combined use of Ferriprox and deferasirox.

The applicant for Deferiprone Lipomed is Lipomed GmbH.

Micrograph showing thalassemia

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for Deferiprone Lipomed to treat iron overload in patients with thalassemia major.

Deferiprone Lipomed is a generic version of the iron chelating agent Ferriprox, which has been authorized in the European Union since August 1999.

According to the CHMP, studies have shown that Deferiprone Lipomed is of satisfactory quality and bioequivalent to Ferriprox.

The CHMP’s recommendation for Deferiprone Lipomed will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Deferiprone Lipomed will be available as 500-mg film-coated tablets.

The drug will be authorized for the following uses:

• As monotherapy to treat iron overload in patients with thalassemia major when current chelation therapy is contraindicated or inadequate
• In combination with another chelator in patients with thalassemia major when monotherapy with any iron chelator is ineffective or when prevention or treatment of life-threatening consequences of iron overload justifies rapid or intensive correction.

According to the prescribing information for Ferriprox, the combination of iron chelators should be considered on a case-by-case basis, and patients should be monitored for response and adverse events.

Fatalities and life-threatening situations (caused by agranulocytosis) have been reported with the combination of deferiprone and deferoxamine.

Combination therapy is not recommended when monotherapy with either chelator is adequate or when serum ferritin falls below 500 μg/l. Additionally, there are limited data on the combined use of Ferriprox and deferasirox.

The applicant for Deferiprone Lipomed is Lipomed GmbH.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).