Anemia

Sickle cell disease (SCD) is an incurable genetic blood disorder that reduces patients’ lifespan and quality of life. Many patients live into their 40s or 50s. Yet, throughout their lives, patients are plagued by lethargy, unpredictable painful crises, and frequent hospitalizations. For nearly 20 years, clinicians only had one drug to treat SCD. Since 2017, three new drugs have been approved, but their costs and lack of long-term data have spawned questions regarding access and benefit.

“SCD reduces lifespan by 30 years, and that’s very hard to quantify,” says Ifeyinwa Osunkwo, MD, professor of medicine and pediatrics and director of Sickle Cell Disease Enterprise at the Levine Cancer Institute at Atrium Health in Charlotte, N.C. “If you put a dollar amount on what someone would make working for 30 adult years, that would be more reflective of the true cost of treating the disease.”

In 1984, hydroxyurea (Hydrea, Droxia) became the first drug to treat SCD in adults.

Originally developed as a myelosuppressive antineoplastic, hydroxyurea is used to treat resistant chronic myeloid leukemia and certain head and neck cancers. In SCD, it increases levels of hemoglobin and fetal hemoglobin.

Despite its benefit, hydroxyurea has two major drawbacks: It is only effective in two genotypes – HbSS or HbS/Beta⁰thal.

HbSS or HbS/Beta⁰thal genotypes account for 60% of the SCD population, but further studies are required to elucidate hydroxyurea’s effect in other forms of SCD, according to Dr. Osunkwo.

Secondly, hydroxyurea only reduces the frequency of painful episodes by 50% – not enough to ameliorate the pain, said John J. Strouse, MD, associate professor of medicine at Duke University School of Medicine.

Newer therapies offer the potential to enhance the effects of hydroxyurea when used concomitantly. They also give clinicians additional options for patients who either fail hydroxyurea therapy or for whom it is inappropriate.

The amino acid L-glutamine (Endari) became the second drug approved for sickle cell in 2017. Indicated for patients 5 years of age and older, Dr. Osunkwo says many patients were thrilled to have a nonchemotherapeutic option available. However, the medical community received the drug with some skepticism. “The data show Endari is moderately effective at best,” said Dr. Strouse. “Also, the mechanism of action is unclear.”

Additionally, the drug’s powder form and twice-daily dosing regimen make adherence more challenging than swallowing a few hydroxyurea tablets or capsules once a day. In Dr. Osunkwo’s experience, patients who respond best to Endari tend to be those who are naturally motivated individuals who are intentional in their efforts at optimizing their nutrition and self-care.

“It takes a lot to be adherent to Endari,” she said. “You have to work at it.”

On Nov. 15, 2019, the FDA approved crizanlizumab-tmca (Adakveo) for patients 16 years of age and older to decrease the occurrence of vasoocclusive crises.

The drug works by blocking selectin – a protein involved in the painful vascular pathophysiology. Patients receive a loading dose of 5 mg/kg administered via intravenous infusion over 30 minutes at the initiation of therapy, as well as weeks 2 and 4. After that, patients undergo treatment once a month. Nausea, back pain, pyrexia, and arthralgia are the most frequently reported adverse reactions. Clinicians must monitor patients for signs and symptoms of infusion-related reactions.

Ten days later, the FDA approved voxelotor (Oxbryta) for patients ages 12 years and up. The drug inhibits hemoglobin S polymerization and increases hemoglobin levels. Like hydroxyurea, the drug offers the convenience of once-daily dosing, and the tablet can be taken without regard to food. The drug dose requires adjustment for patients with severe hepatic impairment. Headache, fatigue, rash, and gastrointestinal disturbances such as diarrhea, nausea, and abdominal pain fall among the most commonly reported side effects.

Endari, Adakveo, and Oxbryta can all be used as monotherapy. They also provide additional benefits in reducing pain and hospitalizations and improving anemia when used concomitantly with hydroxyurea.

Like so many drugs, these novel therapies are expensive. The cost of these novel treatments has raised some eyebrows.

Annual costs of generic hydroxyurea range in the neighborhood of $1,200. In a 2017 CNBC interview, Endari manufacturer Emmaus stated that it aimed to keep drug costs under $20,000 a year. Annual costs for Adakveo and Oxbryta costs are in the neighborhood of $100,000. Adakveo manufacturer Novartis reportedly priced vials at $2,347. Most patients will require at least three of the maximum four vials per treatment. In a press release, Global Therapeutics stated that Oxbyta would cost $10,417 a month.

However, Dr. Osunkwo says the benefits of these new drugs far exceed the costs from both monetary and quality of life standpoints.

“Sickle cell disease is costly to manage,” she said in an interview. “One hospitalization can cost $10,000.”

Additionally, many SCD patients are publicly insured because of the profound disability and loss of productive work they encounter as a direct consequence of their disease and its complications. Those too sick to complete their high school and postsecondary education find limited employment opportunities.

Those fortunate enough to secure employment face significantly fewer years they can work because their pain, fatigue, frequent hospitalizations, and cumulative organ damage result in permanent disability. Only a smaller number of patients with less severe disease manifestations can secure steady employment and pursue careers that allow them to obtain private insurance.

Even if the newer therapies can help cut some costs, clinicians should be aware that prior authorizations can delay patient access to Adakveo and Oxbyta.

“We wrote the first prescription for Oxbryta in November of 2019, but the prior authorization wasn’t approved until February of 2020,” she said. Adding Adakveo to her institution’s formulary required several months of navigation. Given the arduous process, Dr. Osunkwo anticipates it will take at least year after approval before Adakveo is available for all eligible patients.

The long-term impact of these drugs also remains to be seen, so hydroxyurea will likely remain the drug of choice for many patients, according to Dr. Strouse.

Dr. Osunkwo believes SCD needs more drugs in order to truly optimize outcomes, contain costs, and enhance the patient experience.

Dr. Osunkwo reports consultancy and being on the speaker’s bureau and participating in the advisory board for Novartis, which markets Adakveo, and relationships with a variety of other pharmaceutical companies. She is the editor in chief for Hematology News. Dr. Strouse reports consultancy for Global Therapeutics, which markets Oxbryta.

Sickle cell disease (SCD) is an incurable genetic blood disorder that reduces patients’ lifespan and quality of life. Many patients live into their 40s or 50s. Yet, throughout their lives, patients are plagued by lethargy, unpredictable painful crises, and frequent hospitalizations. For nearly 20 years, clinicians only had one drug to treat SCD. Since 2017, three new drugs have been approved, but their costs and lack of long-term data have spawned questions regarding access and benefit.

“SCD reduces lifespan by 30 years, and that’s very hard to quantify,” says Ifeyinwa Osunkwo, MD, professor of medicine and pediatrics and director of Sickle Cell Disease Enterprise at the Levine Cancer Institute at Atrium Health in Charlotte, N.C. “If you put a dollar amount on what someone would make working for 30 adult years, that would be more reflective of the true cost of treating the disease.”

In 1984, hydroxyurea (Hydrea, Droxia) became the first drug to treat SCD in adults.

Originally developed as a myelosuppressive antineoplastic, hydroxyurea is used to treat resistant chronic myeloid leukemia and certain head and neck cancers. In SCD, it increases levels of hemoglobin and fetal hemoglobin.

Despite its benefit, hydroxyurea has two major drawbacks: It is only effective in two genotypes – HbSS or HbS/Beta⁰thal.

HbSS or HbS/Beta⁰thal genotypes account for 60% of the SCD population, but further studies are required to elucidate hydroxyurea’s effect in other forms of SCD, according to Dr. Osunkwo.

Secondly, hydroxyurea only reduces the frequency of painful episodes by 50% – not enough to ameliorate the pain, said John J. Strouse, MD, associate professor of medicine at Duke University School of Medicine.

Newer therapies offer the potential to enhance the effects of hydroxyurea when used concomitantly. They also give clinicians additional options for patients who either fail hydroxyurea therapy or for whom it is inappropriate.

The amino acid L-glutamine (Endari) became the second drug approved for sickle cell in 2017. Indicated for patients 5 years of age and older, Dr. Osunkwo says many patients were thrilled to have a nonchemotherapeutic option available. However, the medical community received the drug with some skepticism. “The data show Endari is moderately effective at best,” said Dr. Strouse. “Also, the mechanism of action is unclear.”

Additionally, the drug’s powder form and twice-daily dosing regimen make adherence more challenging than swallowing a few hydroxyurea tablets or capsules once a day. In Dr. Osunkwo’s experience, patients who respond best to Endari tend to be those who are naturally motivated individuals who are intentional in their efforts at optimizing their nutrition and self-care.

“It takes a lot to be adherent to Endari,” she said. “You have to work at it.”

On Nov. 15, 2019, the FDA approved crizanlizumab-tmca (Adakveo) for patients 16 years of age and older to decrease the occurrence of vasoocclusive crises.

The drug works by blocking selectin – a protein involved in the painful vascular pathophysiology. Patients receive a loading dose of 5 mg/kg administered via intravenous infusion over 30 minutes at the initiation of therapy, as well as weeks 2 and 4. After that, patients undergo treatment once a month. Nausea, back pain, pyrexia, and arthralgia are the most frequently reported adverse reactions. Clinicians must monitor patients for signs and symptoms of infusion-related reactions.

Ten days later, the FDA approved voxelotor (Oxbryta) for patients ages 12 years and up. The drug inhibits hemoglobin S polymerization and increases hemoglobin levels. Like hydroxyurea, the drug offers the convenience of once-daily dosing, and the tablet can be taken without regard to food. The drug dose requires adjustment for patients with severe hepatic impairment. Headache, fatigue, rash, and gastrointestinal disturbances such as diarrhea, nausea, and abdominal pain fall among the most commonly reported side effects.

Endari, Adakveo, and Oxbryta can all be used as monotherapy. They also provide additional benefits in reducing pain and hospitalizations and improving anemia when used concomitantly with hydroxyurea.

Like so many drugs, these novel therapies are expensive. The cost of these novel treatments has raised some eyebrows.

Annual costs of generic hydroxyurea range in the neighborhood of $1,200. In a 2017 CNBC interview, Endari manufacturer Emmaus stated that it aimed to keep drug costs under $20,000 a year. Annual costs for Adakveo and Oxbryta costs are in the neighborhood of $100,000. Adakveo manufacturer Novartis reportedly priced vials at $2,347. Most patients will require at least three of the maximum four vials per treatment. In a press release, Global Therapeutics stated that Oxbyta would cost $10,417 a month.

However, Dr. Osunkwo says the benefits of these new drugs far exceed the costs from both monetary and quality of life standpoints.

“Sickle cell disease is costly to manage,” she said in an interview. “One hospitalization can cost $10,000.”

Additionally, many SCD patients are publicly insured because of the profound disability and loss of productive work they encounter as a direct consequence of their disease and its complications. Those too sick to complete their high school and postsecondary education find limited employment opportunities.

Those fortunate enough to secure employment face significantly fewer years they can work because their pain, fatigue, frequent hospitalizations, and cumulative organ damage result in permanent disability. Only a smaller number of patients with less severe disease manifestations can secure steady employment and pursue careers that allow them to obtain private insurance.

Even if the newer therapies can help cut some costs, clinicians should be aware that prior authorizations can delay patient access to Adakveo and Oxbyta.

“We wrote the first prescription for Oxbryta in November of 2019, but the prior authorization wasn’t approved until February of 2020,” she said. Adding Adakveo to her institution’s formulary required several months of navigation. Given the arduous process, Dr. Osunkwo anticipates it will take at least year after approval before Adakveo is available for all eligible patients.

The long-term impact of these drugs also remains to be seen, so hydroxyurea will likely remain the drug of choice for many patients, according to Dr. Strouse.

Dr. Osunkwo believes SCD needs more drugs in order to truly optimize outcomes, contain costs, and enhance the patient experience.

Dr. Osunkwo reports consultancy and being on the speaker’s bureau and participating in the advisory board for Novartis, which markets Adakveo, and relationships with a variety of other pharmaceutical companies. She is the editor in chief for Hematology News. Dr. Strouse reports consultancy for Global Therapeutics, which markets Oxbryta.

Sickle cell disease (SCD) is an incurable genetic blood disorder that reduces patients’ lifespan and quality of life. Many patients live into their 40s or 50s. Yet, throughout their lives, patients are plagued by lethargy, unpredictable painful crises, and frequent hospitalizations. For nearly 20 years, clinicians only had one drug to treat SCD. Since 2017, three new drugs have been approved, but their costs and lack of long-term data have spawned questions regarding access and benefit.

“SCD reduces lifespan by 30 years, and that’s very hard to quantify,” says Ifeyinwa Osunkwo, MD, professor of medicine and pediatrics and director of Sickle Cell Disease Enterprise at the Levine Cancer Institute at Atrium Health in Charlotte, N.C. “If you put a dollar amount on what someone would make working for 30 adult years, that would be more reflective of the true cost of treating the disease.”

In 1984, hydroxyurea (Hydrea, Droxia) became the first drug to treat SCD in adults.

Originally developed as a myelosuppressive antineoplastic, hydroxyurea is used to treat resistant chronic myeloid leukemia and certain head and neck cancers. In SCD, it increases levels of hemoglobin and fetal hemoglobin.

Despite its benefit, hydroxyurea has two major drawbacks: It is only effective in two genotypes – HbSS or HbS/Beta⁰thal.

HbSS or HbS/Beta⁰thal genotypes account for 60% of the SCD population, but further studies are required to elucidate hydroxyurea’s effect in other forms of SCD, according to Dr. Osunkwo.

Secondly, hydroxyurea only reduces the frequency of painful episodes by 50% – not enough to ameliorate the pain, said John J. Strouse, MD, associate professor of medicine at Duke University School of Medicine.

Newer therapies offer the potential to enhance the effects of hydroxyurea when used concomitantly. They also give clinicians additional options for patients who either fail hydroxyurea therapy or for whom it is inappropriate.

The amino acid L-glutamine (Endari) became the second drug approved for sickle cell in 2017. Indicated for patients 5 years of age and older, Dr. Osunkwo says many patients were thrilled to have a nonchemotherapeutic option available. However, the medical community received the drug with some skepticism. “The data show Endari is moderately effective at best,” said Dr. Strouse. “Also, the mechanism of action is unclear.”

Additionally, the drug’s powder form and twice-daily dosing regimen make adherence more challenging than swallowing a few hydroxyurea tablets or capsules once a day. In Dr. Osunkwo’s experience, patients who respond best to Endari tend to be those who are naturally motivated individuals who are intentional in their efforts at optimizing their nutrition and self-care.

“It takes a lot to be adherent to Endari,” she said. “You have to work at it.”

On Nov. 15, 2019, the FDA approved crizanlizumab-tmca (Adakveo) for patients 16 years of age and older to decrease the occurrence of vasoocclusive crises.

The drug works by blocking selectin – a protein involved in the painful vascular pathophysiology. Patients receive a loading dose of 5 mg/kg administered via intravenous infusion over 30 minutes at the initiation of therapy, as well as weeks 2 and 4. After that, patients undergo treatment once a month. Nausea, back pain, pyrexia, and arthralgia are the most frequently reported adverse reactions. Clinicians must monitor patients for signs and symptoms of infusion-related reactions.

Ten days later, the FDA approved voxelotor (Oxbryta) for patients ages 12 years and up. The drug inhibits hemoglobin S polymerization and increases hemoglobin levels. Like hydroxyurea, the drug offers the convenience of once-daily dosing, and the tablet can be taken without regard to food. The drug dose requires adjustment for patients with severe hepatic impairment. Headache, fatigue, rash, and gastrointestinal disturbances such as diarrhea, nausea, and abdominal pain fall among the most commonly reported side effects.

Endari, Adakveo, and Oxbryta can all be used as monotherapy. They also provide additional benefits in reducing pain and hospitalizations and improving anemia when used concomitantly with hydroxyurea.

Like so many drugs, these novel therapies are expensive. The cost of these novel treatments has raised some eyebrows.

Annual costs of generic hydroxyurea range in the neighborhood of $1,200. In a 2017 CNBC interview, Endari manufacturer Emmaus stated that it aimed to keep drug costs under $20,000 a year. Annual costs for Adakveo and Oxbryta costs are in the neighborhood of $100,000. Adakveo manufacturer Novartis reportedly priced vials at $2,347. Most patients will require at least three of the maximum four vials per treatment. In a press release, Global Therapeutics stated that Oxbyta would cost $10,417 a month.

However, Dr. Osunkwo says the benefits of these new drugs far exceed the costs from both monetary and quality of life standpoints.

“Sickle cell disease is costly to manage,” she said in an interview. “One hospitalization can cost $10,000.”

Additionally, many SCD patients are publicly insured because of the profound disability and loss of productive work they encounter as a direct consequence of their disease and its complications. Those too sick to complete their high school and postsecondary education find limited employment opportunities.

Those fortunate enough to secure employment face significantly fewer years they can work because their pain, fatigue, frequent hospitalizations, and cumulative organ damage result in permanent disability. Only a smaller number of patients with less severe disease manifestations can secure steady employment and pursue careers that allow them to obtain private insurance.

Even if the newer therapies can help cut some costs, clinicians should be aware that prior authorizations can delay patient access to Adakveo and Oxbyta.

“We wrote the first prescription for Oxbryta in November of 2019, but the prior authorization wasn’t approved until February of 2020,” she said. Adding Adakveo to her institution’s formulary required several months of navigation. Given the arduous process, Dr. Osunkwo anticipates it will take at least year after approval before Adakveo is available for all eligible patients.

The long-term impact of these drugs also remains to be seen, so hydroxyurea will likely remain the drug of choice for many patients, according to Dr. Strouse.

Dr. Osunkwo believes SCD needs more drugs in order to truly optimize outcomes, contain costs, and enhance the patient experience.

Dr. Osunkwo reports consultancy and being on the speaker’s bureau and participating in the advisory board for Novartis, which markets Adakveo, and relationships with a variety of other pharmaceutical companies. She is the editor in chief for Hematology News. Dr. Strouse reports consultancy for Global Therapeutics, which markets Oxbryta.

Patients with sickle cell disease (SCD) plus vitamin D deficiency were found to have more hospitalization outcomes, including number of emergency department (ED) visits, the number of hospital admissions for pain crisis, and the length of hospital admission, according to a study published online by researchers from New York-Presbyterian Brooklyn Methodist Hospital.

Dr_Microbe/Thinkstock

The researchers performed a retrospective chart review of all 134 pediatric patients with SCD (aged 1-21 years) from January 2015 to January 2016 in an urban-based hospital setting. Ninety patients with at least one reported vitamin D level who maintained follow-up during the time studied were enrolled. Hospitalization rates were compared between vitamin D deficiency (< 20 ng/mL) and sufficiency (> 20 ng/mL) patients.

When compared to patients with SCD and sufficient vitamin D levels, patients with both SCD and vitamin D deficiency were more likely to have at least one ED visit (P < .01), at least one admission for pain crisis (P < .01), and a longer length of admission (^P < .0001), the researchers found.

“Screening and treatment for vitamin D deficiency is generally cost effective and readily available, potentially having a significant impact on the quality of life for those living with sickle cell disease,” the researchers concluded.

The authors reported that there was no study funding and that they had no conflicts of interest.

[email protected]

SOURCE: Brown B et al. Blood Cells Mol Dis. 2020. doi: 10.1016/j.bcmd.2020.102415.

Patients with sickle cell disease (SCD) plus vitamin D deficiency were found to have more hospitalization outcomes, including number of emergency department (ED) visits, the number of hospital admissions for pain crisis, and the length of hospital admission, according to a study published online by researchers from New York-Presbyterian Brooklyn Methodist Hospital.

Dr_Microbe/Thinkstock

The researchers performed a retrospective chart review of all 134 pediatric patients with SCD (aged 1-21 years) from January 2015 to January 2016 in an urban-based hospital setting. Ninety patients with at least one reported vitamin D level who maintained follow-up during the time studied were enrolled. Hospitalization rates were compared between vitamin D deficiency (< 20 ng/mL) and sufficiency (> 20 ng/mL) patients.

When compared to patients with SCD and sufficient vitamin D levels, patients with both SCD and vitamin D deficiency were more likely to have at least one ED visit (P < .01), at least one admission for pain crisis (P < .01), and a longer length of admission (^P < .0001), the researchers found.

“Screening and treatment for vitamin D deficiency is generally cost effective and readily available, potentially having a significant impact on the quality of life for those living with sickle cell disease,” the researchers concluded.

The authors reported that there was no study funding and that they had no conflicts of interest.

[email protected]

SOURCE: Brown B et al. Blood Cells Mol Dis. 2020. doi: 10.1016/j.bcmd.2020.102415.

Patients with sickle cell disease (SCD) plus vitamin D deficiency were found to have more hospitalization outcomes, including number of emergency department (ED) visits, the number of hospital admissions for pain crisis, and the length of hospital admission, according to a study published online by researchers from New York-Presbyterian Brooklyn Methodist Hospital.

Dr_Microbe/Thinkstock

The researchers performed a retrospective chart review of all 134 pediatric patients with SCD (aged 1-21 years) from January 2015 to January 2016 in an urban-based hospital setting. Ninety patients with at least one reported vitamin D level who maintained follow-up during the time studied were enrolled. Hospitalization rates were compared between vitamin D deficiency (< 20 ng/mL) and sufficiency (> 20 ng/mL) patients.

When compared to patients with SCD and sufficient vitamin D levels, patients with both SCD and vitamin D deficiency were more likely to have at least one ED visit (P < .01), at least one admission for pain crisis (P < .01), and a longer length of admission (^P < .0001), the researchers found.

“Screening and treatment for vitamin D deficiency is generally cost effective and readily available, potentially having a significant impact on the quality of life for those living with sickle cell disease,” the researchers concluded.

The authors reported that there was no study funding and that they had no conflicts of interest.

[email protected]

SOURCE: Brown B et al. Blood Cells Mol Dis. 2020. doi: 10.1016/j.bcmd.2020.102415.

Inferior overall survival was observed in patients with aplastic anemia who had mixed or complete recipient-type chimerism or complete donor chimerism after hematopoietic stem cell transplantation (HSCT), according to the results of a registry database study in Japan.

Researchers examined four groups of patients with AA age greater than 15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation and achieved engraftment.

Group 1 consisted of patients with mixed chimerism (MC) that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support; group 2 consisted of MC (with no secondary graft failure (SGF) that required G-CSF and/or transfusion support ; group 3 consisted of patients with SGF with MC or complete recipient-type chimerism; and group 4 consisted of SGF with complete donor-type chimerism.

The overall median follow-up of survivors was 1,727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In addition, multivariate analyses showed that the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism. The use of Flu in conditioning also was associated with SGF with complete donor-type chimerism.

“The occurrence of SGF with both MC/recipient-type and donor-type chimerism after HSCT for AA was associated with inferior OS, and the conditioning regimens influenced the occurrence of SGF,” the researchers concluded.

The Japan Agency for Medical Research and Development funded the research. Two of the authors reported receiving honoraria or research funding from Sanofi KK and one from Shionogi.

[email protected]

SOURCE: Kako S et al. Biol Blood Marrow Transplant 2020. 26:445-50.

Inferior overall survival was observed in patients with aplastic anemia who had mixed or complete recipient-type chimerism or complete donor chimerism after hematopoietic stem cell transplantation (HSCT), according to the results of a registry database study in Japan.

Researchers examined four groups of patients with AA age greater than 15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation and achieved engraftment.

Group 1 consisted of patients with mixed chimerism (MC) that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support; group 2 consisted of MC (with no secondary graft failure (SGF) that required G-CSF and/or transfusion support ; group 3 consisted of patients with SGF with MC or complete recipient-type chimerism; and group 4 consisted of SGF with complete donor-type chimerism.

The overall median follow-up of survivors was 1,727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In addition, multivariate analyses showed that the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism. The use of Flu in conditioning also was associated with SGF with complete donor-type chimerism.

“The occurrence of SGF with both MC/recipient-type and donor-type chimerism after HSCT for AA was associated with inferior OS, and the conditioning regimens influenced the occurrence of SGF,” the researchers concluded.

The Japan Agency for Medical Research and Development funded the research. Two of the authors reported receiving honoraria or research funding from Sanofi KK and one from Shionogi.

[email protected]

SOURCE: Kako S et al. Biol Blood Marrow Transplant 2020. 26:445-50.

Inferior overall survival was observed in patients with aplastic anemia who had mixed or complete recipient-type chimerism or complete donor chimerism after hematopoietic stem cell transplantation (HSCT), according to the results of a registry database study in Japan.

Researchers examined four groups of patients with AA age greater than 15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation and achieved engraftment.

Group 1 consisted of patients with mixed chimerism (MC) that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support; group 2 consisted of MC (with no secondary graft failure (SGF) that required G-CSF and/or transfusion support ; group 3 consisted of patients with SGF with MC or complete recipient-type chimerism; and group 4 consisted of SGF with complete donor-type chimerism.

The overall median follow-up of survivors was 1,727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In addition, multivariate analyses showed that the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism. The use of Flu in conditioning also was associated with SGF with complete donor-type chimerism.

“The occurrence of SGF with both MC/recipient-type and donor-type chimerism after HSCT for AA was associated with inferior OS, and the conditioning regimens influenced the occurrence of SGF,” the researchers concluded.

The Japan Agency for Medical Research and Development funded the research. Two of the authors reported receiving honoraria or research funding from Sanofi KK and one from Shionogi.

[email protected]

SOURCE: Kako S et al. Biol Blood Marrow Transplant 2020. 26:445-50.

Confirmatory genetic testing may be useful in the diagnosis of hemoglobinopathies for newborns with an abnormal hemoglobin (Hb) pattern, according to a recent study.

The findings suggest further research is needed to evaluate whether genetic testing programs for newborns could have diagnostic value in the clinical setting.

“We studied a consecutive cohort of newborns with an ‘FSA’ pattern (a suspected diagnosis of HbSbeta⁺) on the initial newborn screening test,” explained Lisa M. Shook of the University of Cincinnati and colleagues. The results were published in the International Journal of Neonatal Screening.

The retrospective study included a total of 1,151 newborns with an abnormal Hb pattern, 31 of which had an FSA pattern. The newborns were screened for hemoglobinopathies from 2015 to 2018. The findings of the initial newborn screening test (a suspected diagnosis of HbSbeta⁺) were compared with the diagnosis established using both protein-based and genetic confirmatory testing. Protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when beta-thalassemia mutations are involved, according to the authors.

“During this study period, genetic testing was not universally applied in advance; it was used based on clinical suspicion,” the researchers wrote.

Among newborns with an FSA pattern, the mean gestational age was 38.7 weeks. In total, 17 newborns received genetic testing, and 30 had protein-based confirmatory testing.

“In this consecutive cohort of 31 newborns with a suspected diagnosis of HbSbeta⁺ based on initial newborn screening (an FSA pattern), none actually had HbSbeta⁺. All had the sickle cell trait (HbAS), instead; that is, we found that an initial FSA pattern was much more likely to indicate a final diagnosis of HbAS than HbSbeta⁺,” the authors wrote.

This meant that two-thirds of these newborns had a correct diagnosis of HbAS established at 2-4 weeks of age by protein-based confirmatory testing (and confirmed by genetic testing in a subset), but that the remaining one-third still had an incorrect, suspected diagnosis of HbSbeta⁺. This could lead to unnecessary treatment and testing of infants and incorrect, disease-focused counseling of parents and family members, according to the authors.

Two key limitations of the study were the small sample size and retrospective design.

“Based on this experience in which genetic testing was not universally applied, we now perform simultaneous protein-based and genetic testing as our standard clinical practice,” they concluded.

The study was funded by the National Institutes of Health and the Ohio Department of Health. The authors reported having no conflicts of interest.

SOURCE: Shook LM et al. Int J Neonatal Screen. 2020 Jan 31. doi: 10.3390/ijns6010007

Confirmatory genetic testing may be useful in the diagnosis of hemoglobinopathies for newborns with an abnormal hemoglobin (Hb) pattern, according to a recent study.

The findings suggest further research is needed to evaluate whether genetic testing programs for newborns could have diagnostic value in the clinical setting.

“We studied a consecutive cohort of newborns with an ‘FSA’ pattern (a suspected diagnosis of HbSbeta⁺) on the initial newborn screening test,” explained Lisa M. Shook of the University of Cincinnati and colleagues. The results were published in the International Journal of Neonatal Screening.

The retrospective study included a total of 1,151 newborns with an abnormal Hb pattern, 31 of which had an FSA pattern. The newborns were screened for hemoglobinopathies from 2015 to 2018. The findings of the initial newborn screening test (a suspected diagnosis of HbSbeta⁺) were compared with the diagnosis established using both protein-based and genetic confirmatory testing. Protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when beta-thalassemia mutations are involved, according to the authors.

“During this study period, genetic testing was not universally applied in advance; it was used based on clinical suspicion,” the researchers wrote.

Among newborns with an FSA pattern, the mean gestational age was 38.7 weeks. In total, 17 newborns received genetic testing, and 30 had protein-based confirmatory testing.

“In this consecutive cohort of 31 newborns with a suspected diagnosis of HbSbeta⁺ based on initial newborn screening (an FSA pattern), none actually had HbSbeta⁺. All had the sickle cell trait (HbAS), instead; that is, we found that an initial FSA pattern was much more likely to indicate a final diagnosis of HbAS than HbSbeta⁺,” the authors wrote.

This meant that two-thirds of these newborns had a correct diagnosis of HbAS established at 2-4 weeks of age by protein-based confirmatory testing (and confirmed by genetic testing in a subset), but that the remaining one-third still had an incorrect, suspected diagnosis of HbSbeta⁺. This could lead to unnecessary treatment and testing of infants and incorrect, disease-focused counseling of parents and family members, according to the authors.

Two key limitations of the study were the small sample size and retrospective design.

“Based on this experience in which genetic testing was not universally applied, we now perform simultaneous protein-based and genetic testing as our standard clinical practice,” they concluded.

The study was funded by the National Institutes of Health and the Ohio Department of Health. The authors reported having no conflicts of interest.

SOURCE: Shook LM et al. Int J Neonatal Screen. 2020 Jan 31. doi: 10.3390/ijns6010007

Confirmatory genetic testing may be useful in the diagnosis of hemoglobinopathies for newborns with an abnormal hemoglobin (Hb) pattern, according to a recent study.

The findings suggest further research is needed to evaluate whether genetic testing programs for newborns could have diagnostic value in the clinical setting.

“We studied a consecutive cohort of newborns with an ‘FSA’ pattern (a suspected diagnosis of HbSbeta⁺) on the initial newborn screening test,” explained Lisa M. Shook of the University of Cincinnati and colleagues. The results were published in the International Journal of Neonatal Screening.

The retrospective study included a total of 1,151 newborns with an abnormal Hb pattern, 31 of which had an FSA pattern. The newborns were screened for hemoglobinopathies from 2015 to 2018. The findings of the initial newborn screening test (a suspected diagnosis of HbSbeta⁺) were compared with the diagnosis established using both protein-based and genetic confirmatory testing. Protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when beta-thalassemia mutations are involved, according to the authors.

“During this study period, genetic testing was not universally applied in advance; it was used based on clinical suspicion,” the researchers wrote.

Among newborns with an FSA pattern, the mean gestational age was 38.7 weeks. In total, 17 newborns received genetic testing, and 30 had protein-based confirmatory testing.

“In this consecutive cohort of 31 newborns with a suspected diagnosis of HbSbeta⁺ based on initial newborn screening (an FSA pattern), none actually had HbSbeta⁺. All had the sickle cell trait (HbAS), instead; that is, we found that an initial FSA pattern was much more likely to indicate a final diagnosis of HbAS than HbSbeta⁺,” the authors wrote.

This meant that two-thirds of these newborns had a correct diagnosis of HbAS established at 2-4 weeks of age by protein-based confirmatory testing (and confirmed by genetic testing in a subset), but that the remaining one-third still had an incorrect, suspected diagnosis of HbSbeta⁺. This could lead to unnecessary treatment and testing of infants and incorrect, disease-focused counseling of parents and family members, according to the authors.

Two key limitations of the study were the small sample size and retrospective design.

“Based on this experience in which genetic testing was not universally applied, we now perform simultaneous protein-based and genetic testing as our standard clinical practice,” they concluded.

The study was funded by the National Institutes of Health and the Ohio Department of Health. The authors reported having no conflicts of interest.

SOURCE: Shook LM et al. Int J Neonatal Screen. 2020 Jan 31. doi: 10.3390/ijns6010007

Sonographic flow-mediated dilation (FMD) of the brachial artery predicts renal dysfunction in patients with sickle cell disease (SCD), according to investigators.

Mohammed Haneefa Nizamudeen/Getty Images

This is the first study to show that FMD – a surrogate biomarker for endothelial dysfunction – inversely correlates with renal artery resistivity index (RARI) and serum cystatin C, reported lead author Oluwagbemiga Oluwole Ayoola, MBChB, of Obafemi Awolowo University in Ile-Ife, Nigeria, and colleagues.

“[B]rachial artery FMD is an essential test in the management of SCD patients for noninvasive assessment of the vascular endothelium,” the investigators wrote in Kidney360. They went on to suggest that FMD could be used to detect early renal impairment in sickle cell disease.

The study involved 44 patients with steady-state, homozygous SCD (HbSS) and 33 age- and sex-matched controls (HbAA). Eligibility criteria excluded individuals with risk factors for endothelial dysfunction, such as obesity, diabetes, and hypertension, as well as those with thalassemia carrier traits.

For each participant, various data were gathered, including demographic and clinical characteristics, serum assays, FMD measurement of the brachial artery, and RARI.

Results showed that patients with sickle cell disease had a significantly lower median FMD value than that of healthy controls (3.44 vs. 5.35; P = .043).

Among patients with SCD, FMD was negatively and independently correlated with RARI (r = -.307; P = .042) and serum cystatin C (r = -.372; P = .013), correlations that the investigators described as “modest.” FMD was not associated with any other biomarkers of SCD severity, such as homocysteine, fetal hemoglobin, or soluble platelet selectin.

Patients in the SCD cohort were further subdivided into two groups based on an FMD cut-off value of 5.35, which was the median measurement among healthy controls. This revealed that median cystatin C level was significantly higher in patients with an FMD value less than 5.35, compared with those who had an FMD value of 5.35 or more.

“[The study] findings suggest that SCD patients with impaired FMD are more likely to have impaired renal function,” the investigators wrote. The results support previous research, they added.

“Even though our findings show relationships rather than causation, we believe it is still a step forward in the ongoing quest to unravel the mysteries of this genetic disease,” they concluded. “Determining the exact age at which FMD impairment [begins] in children with sickle cell disease could be the subject of a future study.”

The study was funded by the Obafemi Awolowo University Teaching Hospital. The investigators reported no conflicts of interest.

SOURCE: Ayoola et al. Kidney360. 2020 Jan 30. doi: 10.34067/KID.0000142019.

Sonographic flow-mediated dilation (FMD) of the brachial artery predicts renal dysfunction in patients with sickle cell disease (SCD), according to investigators.

Mohammed Haneefa Nizamudeen/Getty Images

This is the first study to show that FMD – a surrogate biomarker for endothelial dysfunction – inversely correlates with renal artery resistivity index (RARI) and serum cystatin C, reported lead author Oluwagbemiga Oluwole Ayoola, MBChB, of Obafemi Awolowo University in Ile-Ife, Nigeria, and colleagues.

“[B]rachial artery FMD is an essential test in the management of SCD patients for noninvasive assessment of the vascular endothelium,” the investigators wrote in Kidney360. They went on to suggest that FMD could be used to detect early renal impairment in sickle cell disease.

The study involved 44 patients with steady-state, homozygous SCD (HbSS) and 33 age- and sex-matched controls (HbAA). Eligibility criteria excluded individuals with risk factors for endothelial dysfunction, such as obesity, diabetes, and hypertension, as well as those with thalassemia carrier traits.

For each participant, various data were gathered, including demographic and clinical characteristics, serum assays, FMD measurement of the brachial artery, and RARI.

Results showed that patients with sickle cell disease had a significantly lower median FMD value than that of healthy controls (3.44 vs. 5.35; P = .043).

Among patients with SCD, FMD was negatively and independently correlated with RARI (r = -.307; P = .042) and serum cystatin C (r = -.372; P = .013), correlations that the investigators described as “modest.” FMD was not associated with any other biomarkers of SCD severity, such as homocysteine, fetal hemoglobin, or soluble platelet selectin.

Patients in the SCD cohort were further subdivided into two groups based on an FMD cut-off value of 5.35, which was the median measurement among healthy controls. This revealed that median cystatin C level was significantly higher in patients with an FMD value less than 5.35, compared with those who had an FMD value of 5.35 or more.

“[The study] findings suggest that SCD patients with impaired FMD are more likely to have impaired renal function,” the investigators wrote. The results support previous research, they added.

“Even though our findings show relationships rather than causation, we believe it is still a step forward in the ongoing quest to unravel the mysteries of this genetic disease,” they concluded. “Determining the exact age at which FMD impairment [begins] in children with sickle cell disease could be the subject of a future study.”

The study was funded by the Obafemi Awolowo University Teaching Hospital. The investigators reported no conflicts of interest.

SOURCE: Ayoola et al. Kidney360. 2020 Jan 30. doi: 10.34067/KID.0000142019.

Sonographic flow-mediated dilation (FMD) of the brachial artery predicts renal dysfunction in patients with sickle cell disease (SCD), according to investigators.

Mohammed Haneefa Nizamudeen/Getty Images

This is the first study to show that FMD – a surrogate biomarker for endothelial dysfunction – inversely correlates with renal artery resistivity index (RARI) and serum cystatin C, reported lead author Oluwagbemiga Oluwole Ayoola, MBChB, of Obafemi Awolowo University in Ile-Ife, Nigeria, and colleagues.

“[B]rachial artery FMD is an essential test in the management of SCD patients for noninvasive assessment of the vascular endothelium,” the investigators wrote in Kidney360. They went on to suggest that FMD could be used to detect early renal impairment in sickle cell disease.

The study involved 44 patients with steady-state, homozygous SCD (HbSS) and 33 age- and sex-matched controls (HbAA). Eligibility criteria excluded individuals with risk factors for endothelial dysfunction, such as obesity, diabetes, and hypertension, as well as those with thalassemia carrier traits.

For each participant, various data were gathered, including demographic and clinical characteristics, serum assays, FMD measurement of the brachial artery, and RARI.

Results showed that patients with sickle cell disease had a significantly lower median FMD value than that of healthy controls (3.44 vs. 5.35; P = .043).

Among patients with SCD, FMD was negatively and independently correlated with RARI (r = -.307; P = .042) and serum cystatin C (r = -.372; P = .013), correlations that the investigators described as “modest.” FMD was not associated with any other biomarkers of SCD severity, such as homocysteine, fetal hemoglobin, or soluble platelet selectin.

Patients in the SCD cohort were further subdivided into two groups based on an FMD cut-off value of 5.35, which was the median measurement among healthy controls. This revealed that median cystatin C level was significantly higher in patients with an FMD value less than 5.35, compared with those who had an FMD value of 5.35 or more.

“[The study] findings suggest that SCD patients with impaired FMD are more likely to have impaired renal function,” the investigators wrote. The results support previous research, they added.

“Even though our findings show relationships rather than causation, we believe it is still a step forward in the ongoing quest to unravel the mysteries of this genetic disease,” they concluded. “Determining the exact age at which FMD impairment [begins] in children with sickle cell disease could be the subject of a future study.”

The study was funded by the Obafemi Awolowo University Teaching Hospital. The investigators reported no conflicts of interest.

SOURCE: Ayoola et al. Kidney360. 2020 Jan 30. doi: 10.34067/KID.0000142019.

ORLANDO – The oral iron chelator deferiprone showed noninferiority to deferoxamine for treating iron overload in patients with sickle cell disease and other rare anemias in a randomized open-label trial.

The least squares mean change from baseline in liver iron concentration (LIC) – the primary study endpoint – was –4.04 mg/g dry weight (dw) in 152 patients randomized to receive deferiprone, and –4.45 mg/g dw in 76 who received deferoxamine, Janet L. Kwiatkowski, MD, of the Children’s Hospital of Philadelphia reported at the annual meeting of the American Society of Hematology.

The upper limit of the stringent 96.01% confidence interval used for the evaluation of noninferiority in the study was 1.57, thus the findings demonstrated noninferiority of deferiprone, Dr. Kwiatkowski said.

Deferiprone also showed noninferiority for the secondary endpoints of change in cardiac iron (about –0.02 ms on T2* MRI, log-transformed for both groups) and serum ferritin levels (–415 vs. –750 mcg/L for deferiprone vs. deferoxamine) at 12 months. The difference between the groups was not statistically significant for either endpoint.

Study participants, who had a mean age of 16.9 years, were aged 2 years and older with LIC between 7 and 30 mg/g dw. They were recruited from 33 sites in nine countries and randomized 2:1 to receive deferiprone or deferoxamine for up to 12 months; in patients with lower transfusional iron input and/or less severe iron load, deferiprone was dosed at 75 mg/kg daily and deferoxamine was dosed at 20 mg/kg for children and 40 mg/kg for adults. In those with higher iron input and/or more severe iron load, the deferiprone dose was 99 mg/kg daily and the deferoxamine doses were up to 40 mg/kg in children and up to 50 mg/kg for adults.

“Over the course of the treatment period, the dosage could be adjusted downward if there were side effects, or upward if there was no improvement in iron burden,” Dr Kwiatkowski said, adding that after 12 months, patients had the option of continuing on to a 2-year extension trial in which everyone received deferiprone.

No significant demographic differences were noted between the groups; 84% in both groups had sickle cell disease, and the remaining patients had other, rarer forms of transfusion-dependent anemia. Baseline iron burden was similar in the groups.

The rates of acceptable compliance over the course of the study were also similar at 69% and 79% in the deferiprone and deferoxamine arms, respectively, she noted.

No statistically significant difference between the groups was seen in the overall rate of adverse events, treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis occurred in one deferiprone patient and zero deferoxamine patients, and mild or moderate neutropenia occurred in four patients and one patient in the groups, respectively.

All episodes resolved, no difference was seen in the rates of any of the serious AEs, and no unexpected serious adverse events occurred, she said.

Patients with sickle cell disease or other rare anemias whose care includes chronic blood transfusions require iron chelation to prevent iron overload. Currently, only deferoxamine and deferasirox are approved chelators in these patient populations, she said, noting that in 2011 deferiprone received accelerated Food and Drug Administration approval for the treatment of thalassemia.

The current study was conducted because of an FDA requirement for postmarket assessment of deferiprone’s efficacy and safety in patients with sickle cell disease and other anemias who develop transfusional iron overload. It was initiated prior to the approval of deferasirox for the first-line treatment of SCD, therefore it was compared only with deferoxamine, she explained.

Dr. Kwiatkowski reported research funding from Apopharma, bluebird bio, Novartis, and Terumo, and consultancy for Agios, bluebird bio, Celgene, and Imara.

[email protected]

ORLANDO – The oral iron chelator deferiprone showed noninferiority to deferoxamine for treating iron overload in patients with sickle cell disease and other rare anemias in a randomized open-label trial.

The least squares mean change from baseline in liver iron concentration (LIC) – the primary study endpoint – was –4.04 mg/g dry weight (dw) in 152 patients randomized to receive deferiprone, and –4.45 mg/g dw in 76 who received deferoxamine, Janet L. Kwiatkowski, MD, of the Children’s Hospital of Philadelphia reported at the annual meeting of the American Society of Hematology.

The upper limit of the stringent 96.01% confidence interval used for the evaluation of noninferiority in the study was 1.57, thus the findings demonstrated noninferiority of deferiprone, Dr. Kwiatkowski said.

Deferiprone also showed noninferiority for the secondary endpoints of change in cardiac iron (about –0.02 ms on T2* MRI, log-transformed for both groups) and serum ferritin levels (–415 vs. –750 mcg/L for deferiprone vs. deferoxamine) at 12 months. The difference between the groups was not statistically significant for either endpoint.

Study participants, who had a mean age of 16.9 years, were aged 2 years and older with LIC between 7 and 30 mg/g dw. They were recruited from 33 sites in nine countries and randomized 2:1 to receive deferiprone or deferoxamine for up to 12 months; in patients with lower transfusional iron input and/or less severe iron load, deferiprone was dosed at 75 mg/kg daily and deferoxamine was dosed at 20 mg/kg for children and 40 mg/kg for adults. In those with higher iron input and/or more severe iron load, the deferiprone dose was 99 mg/kg daily and the deferoxamine doses were up to 40 mg/kg in children and up to 50 mg/kg for adults.

“Over the course of the treatment period, the dosage could be adjusted downward if there were side effects, or upward if there was no improvement in iron burden,” Dr Kwiatkowski said, adding that after 12 months, patients had the option of continuing on to a 2-year extension trial in which everyone received deferiprone.

No significant demographic differences were noted between the groups; 84% in both groups had sickle cell disease, and the remaining patients had other, rarer forms of transfusion-dependent anemia. Baseline iron burden was similar in the groups.

The rates of acceptable compliance over the course of the study were also similar at 69% and 79% in the deferiprone and deferoxamine arms, respectively, she noted.

No statistically significant difference between the groups was seen in the overall rate of adverse events, treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis occurred in one deferiprone patient and zero deferoxamine patients, and mild or moderate neutropenia occurred in four patients and one patient in the groups, respectively.

All episodes resolved, no difference was seen in the rates of any of the serious AEs, and no unexpected serious adverse events occurred, she said.

Patients with sickle cell disease or other rare anemias whose care includes chronic blood transfusions require iron chelation to prevent iron overload. Currently, only deferoxamine and deferasirox are approved chelators in these patient populations, she said, noting that in 2011 deferiprone received accelerated Food and Drug Administration approval for the treatment of thalassemia.

The current study was conducted because of an FDA requirement for postmarket assessment of deferiprone’s efficacy and safety in patients with sickle cell disease and other anemias who develop transfusional iron overload. It was initiated prior to the approval of deferasirox for the first-line treatment of SCD, therefore it was compared only with deferoxamine, she explained.

Dr. Kwiatkowski reported research funding from Apopharma, bluebird bio, Novartis, and Terumo, and consultancy for Agios, bluebird bio, Celgene, and Imara.

[email protected]

ORLANDO – The oral iron chelator deferiprone showed noninferiority to deferoxamine for treating iron overload in patients with sickle cell disease and other rare anemias in a randomized open-label trial.

The least squares mean change from baseline in liver iron concentration (LIC) – the primary study endpoint – was –4.04 mg/g dry weight (dw) in 152 patients randomized to receive deferiprone, and –4.45 mg/g dw in 76 who received deferoxamine, Janet L. Kwiatkowski, MD, of the Children’s Hospital of Philadelphia reported at the annual meeting of the American Society of Hematology.

The upper limit of the stringent 96.01% confidence interval used for the evaluation of noninferiority in the study was 1.57, thus the findings demonstrated noninferiority of deferiprone, Dr. Kwiatkowski said.

Deferiprone also showed noninferiority for the secondary endpoints of change in cardiac iron (about –0.02 ms on T2* MRI, log-transformed for both groups) and serum ferritin levels (–415 vs. –750 mcg/L for deferiprone vs. deferoxamine) at 12 months. The difference between the groups was not statistically significant for either endpoint.

Study participants, who had a mean age of 16.9 years, were aged 2 years and older with LIC between 7 and 30 mg/g dw. They were recruited from 33 sites in nine countries and randomized 2:1 to receive deferiprone or deferoxamine for up to 12 months; in patients with lower transfusional iron input and/or less severe iron load, deferiprone was dosed at 75 mg/kg daily and deferoxamine was dosed at 20 mg/kg for children and 40 mg/kg for adults. In those with higher iron input and/or more severe iron load, the deferiprone dose was 99 mg/kg daily and the deferoxamine doses were up to 40 mg/kg in children and up to 50 mg/kg for adults.

“Over the course of the treatment period, the dosage could be adjusted downward if there were side effects, or upward if there was no improvement in iron burden,” Dr Kwiatkowski said, adding that after 12 months, patients had the option of continuing on to a 2-year extension trial in which everyone received deferiprone.

No significant demographic differences were noted between the groups; 84% in both groups had sickle cell disease, and the remaining patients had other, rarer forms of transfusion-dependent anemia. Baseline iron burden was similar in the groups.

The rates of acceptable compliance over the course of the study were also similar at 69% and 79% in the deferiprone and deferoxamine arms, respectively, she noted.

No statistically significant difference between the groups was seen in the overall rate of adverse events, treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis occurred in one deferiprone patient and zero deferoxamine patients, and mild or moderate neutropenia occurred in four patients and one patient in the groups, respectively.

All episodes resolved, no difference was seen in the rates of any of the serious AEs, and no unexpected serious adverse events occurred, she said.

Patients with sickle cell disease or other rare anemias whose care includes chronic blood transfusions require iron chelation to prevent iron overload. Currently, only deferoxamine and deferasirox are approved chelators in these patient populations, she said, noting that in 2011 deferiprone received accelerated Food and Drug Administration approval for the treatment of thalassemia.

The current study was conducted because of an FDA requirement for postmarket assessment of deferiprone’s efficacy and safety in patients with sickle cell disease and other anemias who develop transfusional iron overload. It was initiated prior to the approval of deferasirox for the first-line treatment of SCD, therefore it was compared only with deferoxamine, she explained.

Dr. Kwiatkowski reported research funding from Apopharma, bluebird bio, Novartis, and Terumo, and consultancy for Agios, bluebird bio, Celgene, and Imara.

[email protected]

ORLANDO – Sevuparin, a novel nonanticoagulant heparinoid drug, showed no efficacy for acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) in the randomized, controlled, phase 2 TVOC01 trial, but its promising safety and broad mechanism of action warrant further exploration in the prodromal VOC setting, according to investigators.

Dr_Microbe/Thinkstock

Time to VOC resolution – the primary study endpoint – was similar at about 168 hours in 71 hospitalized patients randomized to receive sevuparin and in 76 who received placebo (intention-to-treat hazard ratio, 0.89), Bart J. Biemond, MD, explained during a presentation of the findings at the annual meeting of the American Society of Hematology.

A per-protocol analysis based on the 69 and 75 patients dosed in the treatment and placebo arms, respectively, showed a similar result (HR, 0.81), said Dr. Biemond of the department of clinical hematology, Amsterdam UMC, Academic Medical Center, the Netherlands.

Secondary endpoints, including mean change in pain intensity from baseline on a visual analogue scale (VAS), duration of severest pain measured as time to achieve a 30% reduction in VAS score from baseline, and cumulative use of parenteral opioids, also did not differ between the treatment and placebo arms, he added.

Patients in the global, double-blind, multicenter trial were aged 12-50 years (median, 22 years) with any type of SCD. They were enrolled from 16 sites in 7 countries to receive a loading dose of 3 mg/kg of sevuparin and continuous 18 mg/kg per day infusions or placebo. Patients in both arms also received standard-of-care and parenteral opioid therapy.

The groups were generally balanced with respect to demographic and baseline characteristics, Dr. Biemond said, noting that the treatment was safe: No serious adverse events occurred, and any mild-to-moderate adverse events were transient.

The findings were disappointing given the lack of approved treatment options other than pain management for acute VOC in hospitalized patients with SCD, and they were somewhat surprising given that preclinical and clinical data in recent years have demonstrated that “you can actually prevent those crises by antiadhesive strategies,” he said.

“So we hypothesized that, if you perform such an antiadhesive strategy in a patient already having a crisis and admitted in the hospital, you may shorten their period of admission and perhaps also shorten the severity of their pain,” he said.

In fact, a single-center, randomized, controlled trial conducted by Qari et al. in 2007 (Thromb Haemost. 2007 Aug;98[2]:392-6) showed that full-dose tinzaparin reduced pain severity and duration of admission among sickle cell patients with acute VOC – perhaps because of the antiadhesive properties of heparin – but that study was never repeated, Dr. Biemond said, noting that those antiadhesive properties have been well documented in animal studies.

“Heparin is able to inhibit P-selectin, L-selectin, thrombospondin, fibronectin, and von Willebrand activity, which are all involved in vaso-occlusion in patients with sickle cell disease, and very likely also involved during a vaso-occlusive crisis,” he explained, adding that sevuparin, a low-molecular-weight heparin without functional antithrombin binding domain, seemed to be a good candidate for testing that hypothesis.

“It has no anticoagulant effects on factor Xa and IIa,” he said. “It retains, however, its antiadhesive and antiaggregation properties.”

Since it has no anticoagulation activity, it can be dosed at up to 20-fold the therapeutic dose of low-molecular-weight heparin to optimize the antiadhesive effects, he noted.

However, the data indicate that “antiadhesive therapies are clearly not effective in patients with vaso-occlusive crisis,” he said, noting that this was also affirmed by a similar 2019 study of the investigational panselectin inhibitor rivipansel, as reported in a Pfizer press release.

Intriguingly, the difference between the current study and the 2007 study by Qari et al. raises questions about whether anticoagulation, rather than antiadhesion, helped resolve VOC in that study, he said, noting that future studies should focus on whether that is the case.

As for the role of antiadhesive therapy, the mode of action of sevuparin and the current findings taken together suggest that future studies should also assess whether it can be used to prevent VOC.

“Perhaps sevuparin could be administered to patients in a prodromal phase – just before a real vaso-occlusive crisis appears – to prevent such a crisis from happening,” he said. “It would be interesting to use the drug that way.”

Dr. Biemond reported research funding from Sanquin and honoraria from Novartis and GBT.

[email protected]

SOURCE: Biemond B et al. ASH 2019, Abstract 614.

ORLANDO – Sevuparin, a novel nonanticoagulant heparinoid drug, showed no efficacy for acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) in the randomized, controlled, phase 2 TVOC01 trial, but its promising safety and broad mechanism of action warrant further exploration in the prodromal VOC setting, according to investigators.

Dr_Microbe/Thinkstock

Time to VOC resolution – the primary study endpoint – was similar at about 168 hours in 71 hospitalized patients randomized to receive sevuparin and in 76 who received placebo (intention-to-treat hazard ratio, 0.89), Bart J. Biemond, MD, explained during a presentation of the findings at the annual meeting of the American Society of Hematology.

A per-protocol analysis based on the 69 and 75 patients dosed in the treatment and placebo arms, respectively, showed a similar result (HR, 0.81), said Dr. Biemond of the department of clinical hematology, Amsterdam UMC, Academic Medical Center, the Netherlands.

Secondary endpoints, including mean change in pain intensity from baseline on a visual analogue scale (VAS), duration of severest pain measured as time to achieve a 30% reduction in VAS score from baseline, and cumulative use of parenteral opioids, also did not differ between the treatment and placebo arms, he added.

Patients in the global, double-blind, multicenter trial were aged 12-50 years (median, 22 years) with any type of SCD. They were enrolled from 16 sites in 7 countries to receive a loading dose of 3 mg/kg of sevuparin and continuous 18 mg/kg per day infusions or placebo. Patients in both arms also received standard-of-care and parenteral opioid therapy.

The groups were generally balanced with respect to demographic and baseline characteristics, Dr. Biemond said, noting that the treatment was safe: No serious adverse events occurred, and any mild-to-moderate adverse events were transient.

The findings were disappointing given the lack of approved treatment options other than pain management for acute VOC in hospitalized patients with SCD, and they were somewhat surprising given that preclinical and clinical data in recent years have demonstrated that “you can actually prevent those crises by antiadhesive strategies,” he said.

“So we hypothesized that, if you perform such an antiadhesive strategy in a patient already having a crisis and admitted in the hospital, you may shorten their period of admission and perhaps also shorten the severity of their pain,” he said.

In fact, a single-center, randomized, controlled trial conducted by Qari et al. in 2007 (Thromb Haemost. 2007 Aug;98[2]:392-6) showed that full-dose tinzaparin reduced pain severity and duration of admission among sickle cell patients with acute VOC – perhaps because of the antiadhesive properties of heparin – but that study was never repeated, Dr. Biemond said, noting that those antiadhesive properties have been well documented in animal studies.

“Heparin is able to inhibit P-selectin, L-selectin, thrombospondin, fibronectin, and von Willebrand activity, which are all involved in vaso-occlusion in patients with sickle cell disease, and very likely also involved during a vaso-occlusive crisis,” he explained, adding that sevuparin, a low-molecular-weight heparin without functional antithrombin binding domain, seemed to be a good candidate for testing that hypothesis.

“It has no anticoagulant effects on factor Xa and IIa,” he said. “It retains, however, its antiadhesive and antiaggregation properties.”

Since it has no anticoagulation activity, it can be dosed at up to 20-fold the therapeutic dose of low-molecular-weight heparin to optimize the antiadhesive effects, he noted.

However, the data indicate that “antiadhesive therapies are clearly not effective in patients with vaso-occlusive crisis,” he said, noting that this was also affirmed by a similar 2019 study of the investigational panselectin inhibitor rivipansel, as reported in a Pfizer press release.

Intriguingly, the difference between the current study and the 2007 study by Qari et al. raises questions about whether anticoagulation, rather than antiadhesion, helped resolve VOC in that study, he said, noting that future studies should focus on whether that is the case.

As for the role of antiadhesive therapy, the mode of action of sevuparin and the current findings taken together suggest that future studies should also assess whether it can be used to prevent VOC.

“Perhaps sevuparin could be administered to patients in a prodromal phase – just before a real vaso-occlusive crisis appears – to prevent such a crisis from happening,” he said. “It would be interesting to use the drug that way.”

Dr. Biemond reported research funding from Sanquin and honoraria from Novartis and GBT.

[email protected]

SOURCE: Biemond B et al. ASH 2019, Abstract 614.

ORLANDO – Sevuparin, a novel nonanticoagulant heparinoid drug, showed no efficacy for acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD) in the randomized, controlled, phase 2 TVOC01 trial, but its promising safety and broad mechanism of action warrant further exploration in the prodromal VOC setting, according to investigators.

Dr_Microbe/Thinkstock

Time to VOC resolution – the primary study endpoint – was similar at about 168 hours in 71 hospitalized patients randomized to receive sevuparin and in 76 who received placebo (intention-to-treat hazard ratio, 0.89), Bart J. Biemond, MD, explained during a presentation of the findings at the annual meeting of the American Society of Hematology.

A per-protocol analysis based on the 69 and 75 patients dosed in the treatment and placebo arms, respectively, showed a similar result (HR, 0.81), said Dr. Biemond of the department of clinical hematology, Amsterdam UMC, Academic Medical Center, the Netherlands.

Secondary endpoints, including mean change in pain intensity from baseline on a visual analogue scale (VAS), duration of severest pain measured as time to achieve a 30% reduction in VAS score from baseline, and cumulative use of parenteral opioids, also did not differ between the treatment and placebo arms, he added.

Patients in the global, double-blind, multicenter trial were aged 12-50 years (median, 22 years) with any type of SCD. They were enrolled from 16 sites in 7 countries to receive a loading dose of 3 mg/kg of sevuparin and continuous 18 mg/kg per day infusions or placebo. Patients in both arms also received standard-of-care and parenteral opioid therapy.

The groups were generally balanced with respect to demographic and baseline characteristics, Dr. Biemond said, noting that the treatment was safe: No serious adverse events occurred, and any mild-to-moderate adverse events were transient.

The findings were disappointing given the lack of approved treatment options other than pain management for acute VOC in hospitalized patients with SCD, and they were somewhat surprising given that preclinical and clinical data in recent years have demonstrated that “you can actually prevent those crises by antiadhesive strategies,” he said.

“So we hypothesized that, if you perform such an antiadhesive strategy in a patient already having a crisis and admitted in the hospital, you may shorten their period of admission and perhaps also shorten the severity of their pain,” he said.

In fact, a single-center, randomized, controlled trial conducted by Qari et al. in 2007 (Thromb Haemost. 2007 Aug;98[2]:392-6) showed that full-dose tinzaparin reduced pain severity and duration of admission among sickle cell patients with acute VOC – perhaps because of the antiadhesive properties of heparin – but that study was never repeated, Dr. Biemond said, noting that those antiadhesive properties have been well documented in animal studies.

“Heparin is able to inhibit P-selectin, L-selectin, thrombospondin, fibronectin, and von Willebrand activity, which are all involved in vaso-occlusion in patients with sickle cell disease, and very likely also involved during a vaso-occlusive crisis,” he explained, adding that sevuparin, a low-molecular-weight heparin without functional antithrombin binding domain, seemed to be a good candidate for testing that hypothesis.

“It has no anticoagulant effects on factor Xa and IIa,” he said. “It retains, however, its antiadhesive and antiaggregation properties.”

Since it has no anticoagulation activity, it can be dosed at up to 20-fold the therapeutic dose of low-molecular-weight heparin to optimize the antiadhesive effects, he noted.

However, the data indicate that “antiadhesive therapies are clearly not effective in patients with vaso-occlusive crisis,” he said, noting that this was also affirmed by a similar 2019 study of the investigational panselectin inhibitor rivipansel, as reported in a Pfizer press release.

Intriguingly, the difference between the current study and the 2007 study by Qari et al. raises questions about whether anticoagulation, rather than antiadhesion, helped resolve VOC in that study, he said, noting that future studies should focus on whether that is the case.

As for the role of antiadhesive therapy, the mode of action of sevuparin and the current findings taken together suggest that future studies should also assess whether it can be used to prevent VOC.

“Perhaps sevuparin could be administered to patients in a prodromal phase – just before a real vaso-occlusive crisis appears – to prevent such a crisis from happening,” he said. “It would be interesting to use the drug that way.”

Dr. Biemond reported research funding from Sanquin and honoraria from Novartis and GBT.

[email protected]

SOURCE: Biemond B et al. ASH 2019, Abstract 614.

The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.

Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.

More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.

The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.

Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.

I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.

Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.

The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.

As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
 

Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.

The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.

Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.

More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.

The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.

Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.

I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.

Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.

The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.

As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
 

Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.

The introduction of eculizumab, a monoclonal antibody targeting C5 of the complement cascade, revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and thrombophilia. Treatment options for PNH were limited before eculizumab was approved by the Food and Drug Administration in 2007.

Its use resulted in the inhibition of intravascular hemolysis, hemoglobin stabilization, and substantial reductions in transfusion requirements. Moreover, eculizumab had the unexpected effect of reducing the risk of thromboembolic complications, the most severe complication of PNH. Patients treated with eculizumab experienced fewer thrombotic events (4%), compared with historical cohorts (27%). Importantly, 5-year overall survival rates for patients with PNH taking eculizumab improved more than 90%, compared wity the 80% reported historically.

More than 10 years later, we are tasked with assessing the impact of this drug. Unquestionably, eculizumab has done more for PNH than we could have hoped for. However, 10 years of additional data reveal the limitations of this groundbreaking therapy. Despite the overall sustained response and survival benefit, hematologic response remains variable. Complete normalization of hemoglobin occurs in less than one-third of patients. Transfusion requirements persist in many patients. Residual anemia during eculizumab therapy is at least partly attributed to bone marrow failure, a feature the complement inhibition does not address. Still, pharmacokinetic limitations of the drug also contribute to the lack of complete responses. There is residual intravascular hemolysis because of insufficient inhibition of C5 and the emergence of C3-mediated extravascular hemolysis constitutes an unanticipated mechanistic complication of all C5-mediated therapies.

The last few years have seen a surge in novel anticomplement agents, which improve upon the already well-established inhibition of C5 but also explore the efficacy of targeting earlier aspects of the complement pathway. During the American Society of Hematology (ASH) annual meeting, we had exciting updates on some of the promising new kids on the block.

Ravulizumab, the newest C5 monoclonal antibody approved by the FDA for PNH, displays more robust C5 inhibition, thereby reducing the breakthrough hemolysis still seen with eculizumab use. Crovalimab, also an anti-C5 humanized antibody, is engineered with Sequential Monoclonal Antibody Recycling Technology that improves the half-life of the drug and facilitates subcutaneous dosing while still achieving complete C5 inhibition. Some of the most exciting data is on danicopan, a small-molecule factor D inhibitor that targets the alternative pathway thereby inhibiting C3 convertase and blocking extravascular hemolysis. It has shown promise as a stand-alone agent, as well as with combined C5 inhibition, while promising safety, a reasonable concern as we explore the long-term risks of targeting the proximal complement pathway.

I was recently asked to comment on how the new complement inhibitors are addressing unmet needs in PNH. While the recent presentations at ASH demonstrate an improvement on the efficacy of C5 inhibition, pharmacokinetics, and drug delivery – all which translate to improved hemoglobin and reduced breakthrough hemolysis for PNH patients – I am most excited at the promise this new generation of drugs holds for other diseases. Since its approval for PNH, eculizumab has also been approved for use in atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and neuromyelitis optica spectrum disorder.

Perhaps the greatest potential I envision for the new generation of drugs is in aHUS, a chronic disease characterized by hemolytic anemia, thrombocytopenia, and end-stage renal disease that cannot be cured with renal transplantation. The pathophysiology involves dysregulation of complement activation because of genetic mutations or autoantibodies to key proteins in the complement cascade. Though we have experienced some success with eculizumab, responses can be incomplete, particularly in patients with C5 mutations. The newer drugs offer the opportunity to inhibit complement activation at both proximal and distal aspects of the cascade, which may prove ideal in a disease in which the affected protein is not consistent. Moreover, preclinical and clinical trials have shown promise for these novel complement inhibitors in other autoimmune diseases: antibody-mediated vasculitis, C3 glomerulopathy, catastrophic antibody syndrome, membranous nephropathy, and lupus nephritis.

The surge of new complement inhibitors could revolutionize our strategy for treatment of autoimmune-mediated diseases, in which downstream complement activation can manifest with life-threatening tissue injury. Inhibition of complement offers a promising strategy for blocking downstream immune-mediated effector mechanisms of injury common in several autoimmune diseases.

As the results from various clinical trials come to fruition, it will be exciting to determine how to best use this new generation of drugs to target new diseases and whether the next decade is poised to eclipse the progress in complement therapy already established by eculizumab.
 

Dr. Sosa is a benign hematologist at Fox Chase Cancer Center in Philadelphia. Her research interests are in thromboembolic disease, with a focus in racial and gender disparities.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]

ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.

Sharon Worcester/MDedge News

That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.

The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.

The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.

At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.

The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.

For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.

For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).

Sharon Worcester/MDedge News

Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.

Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.

This is in part because of technical factors, Dr. Desai said.

“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.

As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.

“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.

The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.

Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.

Dr. Liem and Dr. Desai reported having no conflicts of interest.

[email protected]