Anemia

Findings from a phase 3 trial failed to support those from a prior study showing that poloxamer 188 shortened painful vaso-occlusive episodes in sickle cell disease.

Poloxamer 188, a nonionic block polymer surfactant reported to reduce blood viscosity and cell-cell interactions, failed to shorten painful vaso-occlusive episodes in adults and children with sickle cell disease (SCD) in a randomized, placebo-controlled, phase 3 trial.

The findings contrast with those from a prior phase 3 trial showing benefits with treatment, James F. Casella, MD, professor of pediatrics and chief of pediatric hematology at Johns Hopkins University, Baltimore, and colleagues reported.

The time from randomization to the last dose of parenteral opioids in the current study did not differ in 194 patients randomized to the active treatment and 194 randomized to a placebo group (81.8 hours with poloxamer 188 vs. 77.8 hours with placebo), the authors found.

The study results were reported online in JAMA.

Participants in the double-blind study were individuals aged 4-65 years (mean, 15.2 years) with acute moderate to severe painful vaso-occlusive episodes requiring hospitalization. They were recruited between May 2013 and February 2016 from 66 hospitals in 12 countries.

Adverse events that were more common in the poloxamer 188 group included hyperbilirubinemia, which occurred in 12.7% of patients versus 5.2% in the placebo group. Hypoxia occurred more often in the placebo group (12.0% vs. 5.3%).

“Poloxamer 188 has been evaluated in three clinical trials of SCD demonstrating safety and possible efficacy for painful vaso-occlusive episodes and acute chest syndrome, which involves intrapulmonary vascular occlusion and/or infection,” the authors noted. “These studies included a previous phase 3 trial that suggested efficacy for painful vaso-occlusive episodes, particularly in children and participants receiving hydroxyurea.”

The mean duration of vaso-occlusive crisis was reduced by 8.8 hours overall, by 21 hours in those aged under 16 years, and by 16 hours in those receiving hydroxyurea. A small, nonsignificant difference was also seen in the incidence of acute chest syndrome for children in that study.

The findings were encouraging given the lack of disease-modifying therapies for ongoing painful vaso-occlusive episodes, which are associated with higher mortality in patients with SCD; although three agents are available for the prevention vaso-occlusive episodes, including hydroxyurea, L-glutamine, and crizanlizumab-tmca, no available agent effectively manages vaso-occlusive episodes once they have begun, the authors noted.

Current treatment therefore remains supportive, with analgesia and hydration, they added.

This is concerning since “acute pain is estimated to account for 95% of hospital admissions for those with SCD, creating a burden for individuals with SCD, their families, and health care systems,” they explained, adding that the ability to reduce the severity and duration of vaso-occlusive episodes would be a significant advance.

“Because intravenous poloxamer 188 is neither approved by the Food and Drug Administration nor available for clinical use and because other drugs for managing ongoing vaso-occlusive episodes are absent, the present trial was designed to determine whether poloxamer 188 is efficacious for painful vaso-occlusive episodes in SCD,” they said.

However, no benefit was seen for episode duration with treatment in the current study, nor was any beneficial effect on acute chest syndrome observed.

“Rather, although not statistically significant, there were more participants younger than 16 years who developed acute chest syndrome in the poloxamer 188 group than in the placebo group, paralleling the direction of effects on the primary outcome for participants younger than 16 years [in the current study],” they wrote, adding that there were also “no apparent effects on readmission for painful vaso-occlusive episodes in participants receiving hydroxyurea, despite the known effect of hydroxyurea in reducing rates of painful vaso-occlusive episodes and acute chest syndrome.”

Though limited by subjective aspects of assessing the primary outcome in this study and by challenges with effectively blinding poloxamer 188 use, the current findings do not support the use of poloxamer 188 for vaso-occlusive episodes, they concluded.

In an accompanying editorial, JAMA deputy editor Jody Zylke, MD, suggested that the most likely explanation for the differing conclusions in the current and prior phase 3 trials relates to the choice of primary outcome.

In the prior study, the primary outcome was time from randomization to crisis resolution.

“The resolution of pain is subjective, and the criteria to determine crisis resolution established by the investigators were extremely stringent and difficult to implement, leading to a high proportion of participants with incomplete documentation,” Dr. Zylke noted. “Also, incomplete documentation occurred more often in the placebo group than the intervention group, resulting in more imputation of missing values for the placebo group, which favored the poloxamer 188 group.”

In the current trial, a “more easily verified primary outcome was selected, with data available for 99% of participants.”

The report by Dr. Casella and colleagues “adds to the evidence base and illustrates some of the challenges in finding effective treatments for patients with sickle cell disease,” he said.

This study was funded by Mast Therapeutics (previously Adventrx Therapeutics). Dr. Casella reported receiving grants from Mast Therapeutics and receiving an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice to Mast Pharmaceuticals during development of the clinical trial and for serving as the principal investigator for the clinical trial; being an inventor and a named party on a patent and licensing agreement to ImmunArray through Johns Hopkins for a panel of brain biomarkers for the detection of brain injury; and holding a patent for aptamers as a potential treatment for sickle cell disease. Dr. Zylke reported having no disclosures.

[email protected]

Findings from a phase 3 trial failed to support those from a prior study showing that poloxamer 188 shortened painful vaso-occlusive episodes in sickle cell disease.

Poloxamer 188, a nonionic block polymer surfactant reported to reduce blood viscosity and cell-cell interactions, failed to shorten painful vaso-occlusive episodes in adults and children with sickle cell disease (SCD) in a randomized, placebo-controlled, phase 3 trial.

The findings contrast with those from a prior phase 3 trial showing benefits with treatment, James F. Casella, MD, professor of pediatrics and chief of pediatric hematology at Johns Hopkins University, Baltimore, and colleagues reported.

The time from randomization to the last dose of parenteral opioids in the current study did not differ in 194 patients randomized to the active treatment and 194 randomized to a placebo group (81.8 hours with poloxamer 188 vs. 77.8 hours with placebo), the authors found.

The study results were reported online in JAMA.

Participants in the double-blind study were individuals aged 4-65 years (mean, 15.2 years) with acute moderate to severe painful vaso-occlusive episodes requiring hospitalization. They were recruited between May 2013 and February 2016 from 66 hospitals in 12 countries.

Adverse events that were more common in the poloxamer 188 group included hyperbilirubinemia, which occurred in 12.7% of patients versus 5.2% in the placebo group. Hypoxia occurred more often in the placebo group (12.0% vs. 5.3%).

“Poloxamer 188 has been evaluated in three clinical trials of SCD demonstrating safety and possible efficacy for painful vaso-occlusive episodes and acute chest syndrome, which involves intrapulmonary vascular occlusion and/or infection,” the authors noted. “These studies included a previous phase 3 trial that suggested efficacy for painful vaso-occlusive episodes, particularly in children and participants receiving hydroxyurea.”

The mean duration of vaso-occlusive crisis was reduced by 8.8 hours overall, by 21 hours in those aged under 16 years, and by 16 hours in those receiving hydroxyurea. A small, nonsignificant difference was also seen in the incidence of acute chest syndrome for children in that study.

The findings were encouraging given the lack of disease-modifying therapies for ongoing painful vaso-occlusive episodes, which are associated with higher mortality in patients with SCD; although three agents are available for the prevention vaso-occlusive episodes, including hydroxyurea, L-glutamine, and crizanlizumab-tmca, no available agent effectively manages vaso-occlusive episodes once they have begun, the authors noted.

Current treatment therefore remains supportive, with analgesia and hydration, they added.

This is concerning since “acute pain is estimated to account for 95% of hospital admissions for those with SCD, creating a burden for individuals with SCD, their families, and health care systems,” they explained, adding that the ability to reduce the severity and duration of vaso-occlusive episodes would be a significant advance.

“Because intravenous poloxamer 188 is neither approved by the Food and Drug Administration nor available for clinical use and because other drugs for managing ongoing vaso-occlusive episodes are absent, the present trial was designed to determine whether poloxamer 188 is efficacious for painful vaso-occlusive episodes in SCD,” they said.

However, no benefit was seen for episode duration with treatment in the current study, nor was any beneficial effect on acute chest syndrome observed.

“Rather, although not statistically significant, there were more participants younger than 16 years who developed acute chest syndrome in the poloxamer 188 group than in the placebo group, paralleling the direction of effects on the primary outcome for participants younger than 16 years [in the current study],” they wrote, adding that there were also “no apparent effects on readmission for painful vaso-occlusive episodes in participants receiving hydroxyurea, despite the known effect of hydroxyurea in reducing rates of painful vaso-occlusive episodes and acute chest syndrome.”

Though limited by subjective aspects of assessing the primary outcome in this study and by challenges with effectively blinding poloxamer 188 use, the current findings do not support the use of poloxamer 188 for vaso-occlusive episodes, they concluded.

In an accompanying editorial, JAMA deputy editor Jody Zylke, MD, suggested that the most likely explanation for the differing conclusions in the current and prior phase 3 trials relates to the choice of primary outcome.

In the prior study, the primary outcome was time from randomization to crisis resolution.

“The resolution of pain is subjective, and the criteria to determine crisis resolution established by the investigators were extremely stringent and difficult to implement, leading to a high proportion of participants with incomplete documentation,” Dr. Zylke noted. “Also, incomplete documentation occurred more often in the placebo group than the intervention group, resulting in more imputation of missing values for the placebo group, which favored the poloxamer 188 group.”

In the current trial, a “more easily verified primary outcome was selected, with data available for 99% of participants.”

The report by Dr. Casella and colleagues “adds to the evidence base and illustrates some of the challenges in finding effective treatments for patients with sickle cell disease,” he said.

This study was funded by Mast Therapeutics (previously Adventrx Therapeutics). Dr. Casella reported receiving grants from Mast Therapeutics and receiving an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice to Mast Pharmaceuticals during development of the clinical trial and for serving as the principal investigator for the clinical trial; being an inventor and a named party on a patent and licensing agreement to ImmunArray through Johns Hopkins for a panel of brain biomarkers for the detection of brain injury; and holding a patent for aptamers as a potential treatment for sickle cell disease. Dr. Zylke reported having no disclosures.

[email protected]

Findings from a phase 3 trial failed to support those from a prior study showing that poloxamer 188 shortened painful vaso-occlusive episodes in sickle cell disease.

Poloxamer 188, a nonionic block polymer surfactant reported to reduce blood viscosity and cell-cell interactions, failed to shorten painful vaso-occlusive episodes in adults and children with sickle cell disease (SCD) in a randomized, placebo-controlled, phase 3 trial.

The findings contrast with those from a prior phase 3 trial showing benefits with treatment, James F. Casella, MD, professor of pediatrics and chief of pediatric hematology at Johns Hopkins University, Baltimore, and colleagues reported.

The time from randomization to the last dose of parenteral opioids in the current study did not differ in 194 patients randomized to the active treatment and 194 randomized to a placebo group (81.8 hours with poloxamer 188 vs. 77.8 hours with placebo), the authors found.

The study results were reported online in JAMA.

Participants in the double-blind study were individuals aged 4-65 years (mean, 15.2 years) with acute moderate to severe painful vaso-occlusive episodes requiring hospitalization. They were recruited between May 2013 and February 2016 from 66 hospitals in 12 countries.

Adverse events that were more common in the poloxamer 188 group included hyperbilirubinemia, which occurred in 12.7% of patients versus 5.2% in the placebo group. Hypoxia occurred more often in the placebo group (12.0% vs. 5.3%).

“Poloxamer 188 has been evaluated in three clinical trials of SCD demonstrating safety and possible efficacy for painful vaso-occlusive episodes and acute chest syndrome, which involves intrapulmonary vascular occlusion and/or infection,” the authors noted. “These studies included a previous phase 3 trial that suggested efficacy for painful vaso-occlusive episodes, particularly in children and participants receiving hydroxyurea.”

The mean duration of vaso-occlusive crisis was reduced by 8.8 hours overall, by 21 hours in those aged under 16 years, and by 16 hours in those receiving hydroxyurea. A small, nonsignificant difference was also seen in the incidence of acute chest syndrome for children in that study.

The findings were encouraging given the lack of disease-modifying therapies for ongoing painful vaso-occlusive episodes, which are associated with higher mortality in patients with SCD; although three agents are available for the prevention vaso-occlusive episodes, including hydroxyurea, L-glutamine, and crizanlizumab-tmca, no available agent effectively manages vaso-occlusive episodes once they have begun, the authors noted.

Current treatment therefore remains supportive, with analgesia and hydration, they added.

This is concerning since “acute pain is estimated to account for 95% of hospital admissions for those with SCD, creating a burden for individuals with SCD, their families, and health care systems,” they explained, adding that the ability to reduce the severity and duration of vaso-occlusive episodes would be a significant advance.

“Because intravenous poloxamer 188 is neither approved by the Food and Drug Administration nor available for clinical use and because other drugs for managing ongoing vaso-occlusive episodes are absent, the present trial was designed to determine whether poloxamer 188 is efficacious for painful vaso-occlusive episodes in SCD,” they said.

However, no benefit was seen for episode duration with treatment in the current study, nor was any beneficial effect on acute chest syndrome observed.

“Rather, although not statistically significant, there were more participants younger than 16 years who developed acute chest syndrome in the poloxamer 188 group than in the placebo group, paralleling the direction of effects on the primary outcome for participants younger than 16 years [in the current study],” they wrote, adding that there were also “no apparent effects on readmission for painful vaso-occlusive episodes in participants receiving hydroxyurea, despite the known effect of hydroxyurea in reducing rates of painful vaso-occlusive episodes and acute chest syndrome.”

Though limited by subjective aspects of assessing the primary outcome in this study and by challenges with effectively blinding poloxamer 188 use, the current findings do not support the use of poloxamer 188 for vaso-occlusive episodes, they concluded.

In an accompanying editorial, JAMA deputy editor Jody Zylke, MD, suggested that the most likely explanation for the differing conclusions in the current and prior phase 3 trials relates to the choice of primary outcome.

In the prior study, the primary outcome was time from randomization to crisis resolution.

“The resolution of pain is subjective, and the criteria to determine crisis resolution established by the investigators were extremely stringent and difficult to implement, leading to a high proportion of participants with incomplete documentation,” Dr. Zylke noted. “Also, incomplete documentation occurred more often in the placebo group than the intervention group, resulting in more imputation of missing values for the placebo group, which favored the poloxamer 188 group.”

In the current trial, a “more easily verified primary outcome was selected, with data available for 99% of participants.”

The report by Dr. Casella and colleagues “adds to the evidence base and illustrates some of the challenges in finding effective treatments for patients with sickle cell disease,” he said.

This study was funded by Mast Therapeutics (previously Adventrx Therapeutics). Dr. Casella reported receiving grants from Mast Therapeutics and receiving an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice to Mast Pharmaceuticals during development of the clinical trial and for serving as the principal investigator for the clinical trial; being an inventor and a named party on a patent and licensing agreement to ImmunArray through Johns Hopkins for a panel of brain biomarkers for the detection of brain injury; and holding a patent for aptamers as a potential treatment for sickle cell disease. Dr. Zylke reported having no disclosures.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

As individuals with sickle cell disease (SCD) are living longer than ever before there is a greater need to focus on maintaining and improving function and independence in this growing population. In the general population, impairments in functional measures such as usual gait speed, grip strength, Timed Up and Go, and cognition are associated with adverse health outcomes such as falls, fractures, loss of independence, and death.

Adults with SCD experience multiple complications such as avascular necrosis of the joints, retinopathy, and strokes that lead to functional limitations similar to those experienced by geriatric populations. However, functional assessments are not routinely performed during clinic visits with older adults with SCD.

In order to address this gap in care, my colleagues and I developed the first functional assessment for older adults with SCD, called the Sickle Cell Disease Functional Assessment (SCD-FA). This assessment will allow providers to evaluate the capabilities and vulnerabilities of older adults with SCD.

We assessed the feasibility of administering the SCD-FA in a prospective cohort pilot study. We enrolled 40 adults with SCD (20 older adults aged at least 50 years and 20 younger adults aged 18-49 years as a comparison group). All participants were assessed at steady-state.

For the SCD-FA, we selected geriatric assessment measures across seven domains: functional status, comorbid medical conditions, psychological state, social support, nutritional status, cognition, and medications. Several of these measures were previously validated in an oncology geriatric assessment and enriched with additional physical and cognitive measures to evaluate conditions at the intersection of SCD and geriatrics.

In September 2020, we published a protocol describing the methods and rationale for selecting measures for the SCD-FA in Pilot and Feasibility Studies.¹ The preliminary data was presented at the annual meeting of the American Society of Hematology in December 2020 and was included in the annual Hematology and Aging Poster Walk.

The results of this pilot study showed that the SCD-FA is feasible (91% of participants who consented completed the SCD-FA), acceptable (95% reported the length as appropriate and had no difficulty understanding the measures), and safe with no adverse events.² On physical performance testing, both younger and older participants had results consistent with accelerated aging with a functional age at least 20-30 years older than their chronological age.²

The majority of the participants (63%) had a usual gait speed slower than the speed required to safely cross the street at an intersection, and 25% had a gait speed slower than 1 m/s, which has been associated with increased mortality in the general population.^3,4
 

Benefits to management

The SCD-FA can improve management of adults with SCD by:

• Characterizing their capabilities and physiological age, identifying individuals at high risk for functional decline and death early identifying targets for interventions that have been successful in geriatrics,⁵ assessing risk of toxicity from curative therapies, and evaluating functional response to SCD-specific therapies.

The SCD-FA provides a framework for developing exercise interventions to target functional impairments. This work supports our goal of improving the quality of life and longevity for people with SCD.

Dr. Oyedeji is a senior hematology Fellow at the department of medicine, division of hematology, Duke University, Durham, N.C. She reported that she has no conflicts of interest.

References

1. Pilot Feasibility Stud. 2020;6:131.

2. Blood. 2020;136(Supplement 1):26-7.

3. J Rehabil Res Dev. 2005;42(4):535-46.

4. JAMA. 2011;305(1):50-8.

5. South Med J. 1994;87(5):S83-7.

As individuals with sickle cell disease (SCD) are living longer than ever before there is a greater need to focus on maintaining and improving function and independence in this growing population. In the general population, impairments in functional measures such as usual gait speed, grip strength, Timed Up and Go, and cognition are associated with adverse health outcomes such as falls, fractures, loss of independence, and death.

Adults with SCD experience multiple complications such as avascular necrosis of the joints, retinopathy, and strokes that lead to functional limitations similar to those experienced by geriatric populations. However, functional assessments are not routinely performed during clinic visits with older adults with SCD.

In order to address this gap in care, my colleagues and I developed the first functional assessment for older adults with SCD, called the Sickle Cell Disease Functional Assessment (SCD-FA). This assessment will allow providers to evaluate the capabilities and vulnerabilities of older adults with SCD.

We assessed the feasibility of administering the SCD-FA in a prospective cohort pilot study. We enrolled 40 adults with SCD (20 older adults aged at least 50 years and 20 younger adults aged 18-49 years as a comparison group). All participants were assessed at steady-state.

For the SCD-FA, we selected geriatric assessment measures across seven domains: functional status, comorbid medical conditions, psychological state, social support, nutritional status, cognition, and medications. Several of these measures were previously validated in an oncology geriatric assessment and enriched with additional physical and cognitive measures to evaluate conditions at the intersection of SCD and geriatrics.

In September 2020, we published a protocol describing the methods and rationale for selecting measures for the SCD-FA in Pilot and Feasibility Studies.¹ The preliminary data was presented at the annual meeting of the American Society of Hematology in December 2020 and was included in the annual Hematology and Aging Poster Walk.

The results of this pilot study showed that the SCD-FA is feasible (91% of participants who consented completed the SCD-FA), acceptable (95% reported the length as appropriate and had no difficulty understanding the measures), and safe with no adverse events.² On physical performance testing, both younger and older participants had results consistent with accelerated aging with a functional age at least 20-30 years older than their chronological age.²

The majority of the participants (63%) had a usual gait speed slower than the speed required to safely cross the street at an intersection, and 25% had a gait speed slower than 1 m/s, which has been associated with increased mortality in the general population.^3,4
 

Benefits to management

The SCD-FA can improve management of adults with SCD by:

• Characterizing their capabilities and physiological age, identifying individuals at high risk for functional decline and death early identifying targets for interventions that have been successful in geriatrics,⁵ assessing risk of toxicity from curative therapies, and evaluating functional response to SCD-specific therapies.

The SCD-FA provides a framework for developing exercise interventions to target functional impairments. This work supports our goal of improving the quality of life and longevity for people with SCD.

Dr. Oyedeji is a senior hematology Fellow at the department of medicine, division of hematology, Duke University, Durham, N.C. She reported that she has no conflicts of interest.

References

1. Pilot Feasibility Stud. 2020;6:131.

2. Blood. 2020;136(Supplement 1):26-7.

3. J Rehabil Res Dev. 2005;42(4):535-46.

4. JAMA. 2011;305(1):50-8.

5. South Med J. 1994;87(5):S83-7.

As individuals with sickle cell disease (SCD) are living longer than ever before there is a greater need to focus on maintaining and improving function and independence in this growing population. In the general population, impairments in functional measures such as usual gait speed, grip strength, Timed Up and Go, and cognition are associated with adverse health outcomes such as falls, fractures, loss of independence, and death.

Adults with SCD experience multiple complications such as avascular necrosis of the joints, retinopathy, and strokes that lead to functional limitations similar to those experienced by geriatric populations. However, functional assessments are not routinely performed during clinic visits with older adults with SCD.

In order to address this gap in care, my colleagues and I developed the first functional assessment for older adults with SCD, called the Sickle Cell Disease Functional Assessment (SCD-FA). This assessment will allow providers to evaluate the capabilities and vulnerabilities of older adults with SCD.

We assessed the feasibility of administering the SCD-FA in a prospective cohort pilot study. We enrolled 40 adults with SCD (20 older adults aged at least 50 years and 20 younger adults aged 18-49 years as a comparison group). All participants were assessed at steady-state.

For the SCD-FA, we selected geriatric assessment measures across seven domains: functional status, comorbid medical conditions, psychological state, social support, nutritional status, cognition, and medications. Several of these measures were previously validated in an oncology geriatric assessment and enriched with additional physical and cognitive measures to evaluate conditions at the intersection of SCD and geriatrics.

In September 2020, we published a protocol describing the methods and rationale for selecting measures for the SCD-FA in Pilot and Feasibility Studies.¹ The preliminary data was presented at the annual meeting of the American Society of Hematology in December 2020 and was included in the annual Hematology and Aging Poster Walk.

The results of this pilot study showed that the SCD-FA is feasible (91% of participants who consented completed the SCD-FA), acceptable (95% reported the length as appropriate and had no difficulty understanding the measures), and safe with no adverse events.² On physical performance testing, both younger and older participants had results consistent with accelerated aging with a functional age at least 20-30 years older than their chronological age.²

The majority of the participants (63%) had a usual gait speed slower than the speed required to safely cross the street at an intersection, and 25% had a gait speed slower than 1 m/s, which has been associated with increased mortality in the general population.^3,4
 

Benefits to management

The SCD-FA can improve management of adults with SCD by:

• Characterizing their capabilities and physiological age, identifying individuals at high risk for functional decline and death early identifying targets for interventions that have been successful in geriatrics,⁵ assessing risk of toxicity from curative therapies, and evaluating functional response to SCD-specific therapies.

The SCD-FA provides a framework for developing exercise interventions to target functional impairments. This work supports our goal of improving the quality of life and longevity for people with SCD.

Dr. Oyedeji is a senior hematology Fellow at the department of medicine, division of hematology, Duke University, Durham, N.C. She reported that she has no conflicts of interest.

References

1. Pilot Feasibility Stud. 2020;6:131.

2. Blood. 2020;136(Supplement 1):26-7.

3. J Rehabil Res Dev. 2005;42(4):535-46.

4. JAMA. 2011;305(1):50-8.

5. South Med J. 1994;87(5):S83-7.

Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.

The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.

Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.

“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”

The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.

FTX-6058 was designed to mimic this effect.

FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.

Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
 

Ongoing studies

The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.

The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.

The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.

Fulcrum Therapeutics is funding the studies.

[email protected]

Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.

The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.

Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.

“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”

The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.

FTX-6058 was designed to mimic this effect.

FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.

Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
 

Ongoing studies

The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.

The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.

The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.

Fulcrum Therapeutics is funding the studies.

[email protected]

Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.

The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.

Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.

“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”

The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.

FTX-6058 was designed to mimic this effect.

FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.

Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.
 

Ongoing studies

The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.

The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.

The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.

Fulcrum Therapeutics is funding the studies.

[email protected]

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers ([email protected]).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

[email protected]

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers ([email protected]).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

[email protected]

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers ([email protected]).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

[email protected]

The Food and Drug Administration placed a clinical hold yesterday on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.

The company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.

Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.

The gene therapy “space” is one with spectacular successes – for a form of retinal blindness and spinal muscular atrophy – rising against a backdrop of recent setbacks and failures – for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.
 

A lentiviral vector

The retooled lentivirus used in the SCD trials, LentiGlobin, delivers a beta-globin gene with one amino acid replacement to hematopoietic stem cells outside the patient’s body. The modified cells are then infused back into the patient. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.

What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.

The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.

Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.

Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.

Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.

Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”
 

Pinpointing causality

At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”

Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.

In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.

Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
 

A patient’s view

SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy

Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.

Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.

“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration placed a clinical hold yesterday on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.

The company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.

Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.

The gene therapy “space” is one with spectacular successes – for a form of retinal blindness and spinal muscular atrophy – rising against a backdrop of recent setbacks and failures – for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.
 

A lentiviral vector

The retooled lentivirus used in the SCD trials, LentiGlobin, delivers a beta-globin gene with one amino acid replacement to hematopoietic stem cells outside the patient’s body. The modified cells are then infused back into the patient. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.

What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.

The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.

Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.

Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.

Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.

Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”
 

Pinpointing causality

At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”

Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.

In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.

Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
 

A patient’s view

SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy

Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.

Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.

“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration placed a clinical hold yesterday on two gene therapy trials for sickle cell disease (SCD) after two recent complications: one participant developed acute myeloid leukemia (AML) and another developed myelodysplastic syndrome (MDS). The sponsoring company, bluebird bio, suspended the trials last week upon learning of the cases.

The company has also put the brakes on a treatment for beta thalassemia already approved in the European Union and the United Kingdom, betibeglogene autotemcel (Zynteglo). The treatment hasn’t been associated with problems but uses the same gene delivery vector, a lentivirus, as that used in the SCD trials.

Overall, the company has enrolled 47 SCD patients and 63 with beta thalassemia in trials.

The gene therapy “space” is one with spectacular successes – for a form of retinal blindness and spinal muscular atrophy – rising against a backdrop of recent setbacks and failures – for Duchenne muscular dystrophy, lipoprotein lipase deficiency, and myotubular myopathy.
 

A lentiviral vector

The retooled lentivirus used in the SCD trials, LentiGlobin, delivers a beta-globin gene with one amino acid replacement to hematopoietic stem cells outside the patient’s body. The modified cells are then infused back into the patient. The gene therapy reshapes red blood cells, enabling them to circulate through narrow blood vessels without sickling and adhering into painful logjams.

What is worrisome is that in the patient who developed AML, and who received the gene therapy more than 5 years ago, the cancer cells contained the vector. Those test results aren’t yet available for the participant who has MDS.

The finding raises suspicion that the gene therapy had a role in the cancer, but is only correlative.

Lentiviral vectors have a good track record, but the two cases evoke memories of 2 decades ago. In 2001, five children being treated for an inherited immunodeficiency (SCID-X1) with a gamma retroviral vector developed leukemia and one died. Those viruses inserted into an oncogene. Happening 2 years after the death of 18-year-old Jesse Gelsinger in another gene therapy trial, the SCID trial had a chilling effect on the field.

Since then, lentiviral vectors have been reinvented to be “self-inactivating,” minimizing the risk for inserting willy-nilly into a genome. “Lentiviral vectors have been expressly designed to avoid insertional oncogenesis, based on prior experience with the gamma retroviruses. We don’t have evidence that the vector is causative, but our studies will shed some light on whether that’s true in these cases,” said bluebird bio chief scientific officer Philip Gregory, DPhil, on a conference call Feb. 16.

Lentiviral vectors have been successful as the backbone of chimeric antigen receptor T-cell (CAR-T) therapy, which directs modified T cells to certain blood cancers. “Among the hundreds to thousands of patients treated with CAR-T cell therapy, lentivirus vector hasn’t been associated with any malignancies,” said bluebird’s chief medical officer, Dave Davidson, MD.

Jeanne Loring, PhD, director of the Center for Regenerative Medicine at Scripps Research, agreed. “Gene therapy is having some extreme highs and lows these days. Most studies use [adeno-associated viral] vectors, which don’t integrate into the genome. But some people have antibodies to AAV vectors, and AAV is diluted out when cells divide. That’s why lentivirus, which integrates into the genome, is used for blood stem cells and T cells in CAR-T therapy.”
 

Pinpointing causality

At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”

Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.

In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.

Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
 

A patient’s view

SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy

Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.

Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.

“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”

A version of this article first appeared on Medscape.com.

The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.

Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.

“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.

Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.

“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
 

Anxiety and catastrophizing

Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.

The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.

They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.

Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.

Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.

The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).

The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,

The median number of hospital admissions for pain was zero and one, respectively.
 

Attention, emotions linked to higher use

Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).

Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).

There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.

The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
 

Age-related differences?

In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.

“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.

Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.

Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.

Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”

The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.

SOURCE: Williams Z et al. ASH 2020, Abstract 366

The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.

Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.

“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.

Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.

“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
 

Anxiety and catastrophizing

Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.

The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.

They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.

Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.

Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.

The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).

The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,

The median number of hospital admissions for pain was zero and one, respectively.
 

Attention, emotions linked to higher use

Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).

Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).

There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.

The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
 

Age-related differences?

In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.

“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.

Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.

Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.

Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”

The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.

SOURCE: Williams Z et al. ASH 2020, Abstract 366

The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.

Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.

“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.

Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.

“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
 

Anxiety and catastrophizing

Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.

The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.

They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.

Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.

Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.

The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).

The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,

The median number of hospital admissions for pain was zero and one, respectively.
 

Attention, emotions linked to higher use

Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).

Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).

There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.

The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
 

Age-related differences?

In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.

“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.

Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.

Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.

Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”

The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.

SOURCE: Williams Z et al. ASH 2020, Abstract 366

The National Academies of Science, Engineering, and Medicine have just released a 522-page report, but it’s not the usual compilation of guidelines for treatment of a disease. Instead, the authors of “Addressing Sickle Cell Disease: A Strategic Plan and Blueprint for Action” argue in stark terms that the American society has colossally failed individuals living with sickle cell disease (SCD), who are mostly Black or Brown. A dramatic overhaul of the country’s medical and societal priorities is needed to turn things around to improve health and longevity among this rare disease population.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

The findings from the NASEM report are explicit: “There has been substantial success in increasing the survival of children with SCD, but this success had not been translated to similar success as they become adults.” One factor posited to contribute to the slow progress in the improvement of quality and quantity of life for adults living with this disease is the fact that “SCD is largely a disease of African Americans, and as such exists in a context of racial discrimination, health and other societal disparities, mistrust of the health care system, and the effects of poverty.” The report also cites the substantial evidence that those with SCD may receive poorer quality of care.

The report’s 14 authors were made up of an ad hoc committee formed at the request of the Department of Health & Human Services’ Office of Minority Health. The office asked NASEM to convene the committee to develop a strategic plan and blueprint for the United States and others regarding SCD.

The NASEM SCD committee members “realized that we can’t address the medical components of SCD if we don’t explore societal issues and why it’s been so hard to get good care for people with sickle cell disease,” hematologist and report coauthor Ifeyinwa (Ify) Osunkwo, MD, professor of medicine and pediatrics at Atrium Health and director of the Sickle Cell Disease Enterprise, Levine Cancer Institute, Charlotte, N.C., said in an interview. Dr. Osunkwo is also the medical editor of Hematology News.

“After almost a year of meetings and digging into the background and history of SCD care, we came out with very comprehensive summary of where we were and where we want to be,” she said. “The report provides short-, intermediate- and long-term recommendations and identifies which entity and organization should be responsible for implementing them.”

The report authors, led by pediatrician and committee chair Marie Clare McCormick, MD, of the Harvard School of Public Health, Boston, stated that about 100,000 people in the United States and millions worldwide live with SCD. The disease kills more than 700 people per year in the United States, and treatment costs an estimated $2 billion a year.

When judged by disability-adjusted life-years lost – a measurement of expected healthy years of life without an illness – the impact of SCD on individuals is estimated to be greater than a long list of other diseases such as Alzheimer’s disease, breast cancer, type 1 diabetes, and AIDS/HIV, the report noted.

“The health care needs of individuals living with SCD have been neglected by the U.S. and global health care systems, causing them and their families to suffer,” the report said. “Many of the complications that afflict individuals with SCD, particularly pain, are invisible. Pain is only diagnosed by self-reports, and in SCD there are few to no external indicators of the pain experience. Nevertheless, the pain can be excruciatingly severe and requires treatment with strong analgesics.”

There’s even more misery to the story of SCD, the report said, and Dr. Osunkwo agreed. “It’s not just about pain. These individuals suffer from multiple organ-system complications that are physical but also psychological and societal. They experience a lot of disparities in every aspect of their lives. You’re sick, so then you can’t get a job or health insurance, you can’t get Social Security benefits. You can’t get the type of health care you need nor can you access the other forms of support you need and often you are judged as a drug seeker for complaining of pain or repeatedly seeking acute care for unresolved pain.”

Multiple factors exacerbate the experience of people living with SCD in America, the report said. “Because of systemic racism, unconscious bias, and the stigma associated with the diagnosis, the disease brings with it a much broader burden.”

Dr. Osunkwo put it this way: “SCD is a disease that mostly affects Brown and Black people, and that gets layered into the whole discrimination issues that Black and Brown people face compounding the health burden from their disease.”

The report added that “the SCD community has developed a significant lack of trust in the health care system due to the nearly universal stigma and lack of belief in their reports of pain, a lack of trust that has been further reinforced by historical events, such as the Tuskegee experiment.”

The report highlighted research that finds that Blacks “are more likely to receive a lower quality of pain management than white patients and may be perceived as having drug-seeking behavior.”

The report also identified gaps in treatment, noting that “many SCD complications are not restricted to any one organ system, and the impact of the disease on [quality of life] can be profound but hard to define and compartmentalize.”

Dr. Osunkwo said medical professionals often fail to understand the full breadth of the disease. “There’s no particular look to SCD. When you have cancer, you come in, and you look like you’re sick because you’re bald. Everyone clues into that cancer look and knows it’s lethal, that you’re may likely die early. We don’t have that “look that generates empathy” for SCD, and people don’t understand the burden on those affected. They don’t understand or appreciate that SCD shortens your lifespan as well ... that people living with SCD die 3 decades earlier than their ethnically matched peers. Also, SCD is associated with a lot of pain, and pain and the treatment of pain with opioids makes people [health care providers] uncomfortable unless it’s cancer pain.”

She added: “People also assume that, if it’s not pain, it’s not SCD even though SCD can cause leg ulcers and blood clots and even affect the tonsils, or lead to a stroke. When a disease complexity is too difficult for providers to understand, they either avoid it or don’t do anything for the patient.”

Screening and surveillance for SCD and sickle cell trait is insufficient, the report said, and the potential cost of missed childhood cases is large. Detecting the condition at birth allows the implementation of appropriate comprehensive care and treatment to prevent early death from infections and strokes. As the authors noted, “tremendous strides have been made in the past few decades in the care of children with SCD, which have led to almost all children in high-income settings surviving to adulthood.” However, there remains gaps in care coordination and follow-up of babies screened at birth and even bigger gaps in translating these life span gains to adults particularly around the period of transition from pediatrics to adult care when there appears to be a spike in morbidity and mortality.

Dr_Microbe/Thinkstock

The report summarized current treatments for SCD and noted “an influx of pipeline products” after years of little progress and identifies “a need for targeted SCD therapies that address the underlying cause of the disease.”

While treatment recommendations exist, Dr. Osunkwo said, “the evidence for them is very poor and many SCD complications have no evidence-based guidelines for providers to follow. We need more research to provide high quality evidence to make guidelines for SCD treatment stronger and more robust.”

In its final section, the report offers a “strategic plan and blueprint for sickle cell disease action.” It offers several strategies to achieve the vision of “long healthy productive lives for those living with sickle cell disease and sickle cell trait”:

• Establish and fund a research agenda to inform effective programs and policies across the life span.
• Implement efforts to advance understanding of the full impact of sickle cell trait on individuals and society.
• Address barriers to accessing current and pipeline therapies for SCD.
• Improve SCD awareness and strengthen advocacy efforts.
• Increase the number of qualified health professionals providing SCD care.
• Strengthen the evidence base for interventions and disease management and implement widespread efforts to monitor the quality of SCD care.
• Establish organized systems of care assuring both clinical and nonclinical supportive services to all persons living with SCD.
• Establish a national system to collect and link data to characterize the burden of disease, outcomes, and the needs of those with SCD across the life span.

“Right now, the average lifespan for SCD is in the mid-40s to mid-50s,” Dr. Osunkwo said. “That’s a horrible statistic. Even if we just take up half of these recommendations, people will live longer with SCD, and they’ll be more productive and contribute more to society. If we value a cancer life the same as a sickle cell life, we’ll be halfway across the finish line. But the stigma of SCD being a Black and Brown problem is going to be the hardest to confront as it requires a systemic change in our culture as a country and a health care system.”

Still, she said, the commissioning of the report “shows that there is a desire to understand the issue in better detail and try to mitigate it.”

Dr. Osunkwo and Dr. McCormick had no relevant disclosures.

SOURCE: National Academies of Sciences, Engineering, and Medicine. Addressing Sickle Cell Disease: A Strategic Plan and Blueprint for Action. Washington, D.C.: National Academies Press, 2020.

The National Academies of Science, Engineering, and Medicine have just released a 522-page report, but it’s not the usual compilation of guidelines for treatment of a disease. Instead, the authors of “Addressing Sickle Cell Disease: A Strategic Plan and Blueprint for Action” argue in stark terms that the American society has colossally failed individuals living with sickle cell disease (SCD), who are mostly Black or Brown. A dramatic overhaul of the country’s medical and societal priorities is needed to turn things around to improve health and longevity among this rare disease population.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

The findings from the NASEM report are explicit: “There has been substantial success in increasing the survival of children with SCD, but this success had not been translated to similar success as they become adults.” One factor posited to contribute to the slow progress in the improvement of quality and quantity of life for adults living with this disease is the fact that “SCD is largely a disease of African Americans, and as such exists in a context of racial discrimination, health and other societal disparities, mistrust of the health care system, and the effects of poverty.” The report also cites the substantial evidence that those with SCD may receive poorer quality of care.

The report’s 14 authors were made up of an ad hoc committee formed at the request of the Department of Health & Human Services’ Office of Minority Health. The office asked NASEM to convene the committee to develop a strategic plan and blueprint for the United States and others regarding SCD.

The NASEM SCD committee members “realized that we can’t address the medical components of SCD if we don’t explore societal issues and why it’s been so hard to get good care for people with sickle cell disease,” hematologist and report coauthor Ifeyinwa (Ify) Osunkwo, MD, professor of medicine and pediatrics at Atrium Health and director of the Sickle Cell Disease Enterprise, Levine Cancer Institute, Charlotte, N.C., said in an interview. Dr. Osunkwo is also the medical editor of Hematology News.

“After almost a year of meetings and digging into the background and history of SCD care, we came out with very comprehensive summary of where we were and where we want to be,” she said. “The report provides short-, intermediate- and long-term recommendations and identifies which entity and organization should be responsible for implementing them.”

The report authors, led by pediatrician and committee chair Marie Clare McCormick, MD, of the Harvard School of Public Health, Boston, stated that about 100,000 people in the United States and millions worldwide live with SCD. The disease kills more than 700 people per year in the United States, and treatment costs an estimated $2 billion a year.

When judged by disability-adjusted life-years lost – a measurement of expected healthy years of life without an illness – the impact of SCD on individuals is estimated to be greater than a long list of other diseases such as Alzheimer’s disease, breast cancer, type 1 diabetes, and AIDS/HIV, the report noted.

“The health care needs of individuals living with SCD have been neglected by the U.S. and global health care systems, causing them and their families to suffer,” the report said. “Many of the complications that afflict individuals with SCD, particularly pain, are invisible. Pain is only diagnosed by self-reports, and in SCD there are few to no external indicators of the pain experience. Nevertheless, the pain can be excruciatingly severe and requires treatment with strong analgesics.”

There’s even more misery to the story of SCD, the report said, and Dr. Osunkwo agreed. “It’s not just about pain. These individuals suffer from multiple organ-system complications that are physical but also psychological and societal. They experience a lot of disparities in every aspect of their lives. You’re sick, so then you can’t get a job or health insurance, you can’t get Social Security benefits. You can’t get the type of health care you need nor can you access the other forms of support you need and often you are judged as a drug seeker for complaining of pain or repeatedly seeking acute care for unresolved pain.”

Multiple factors exacerbate the experience of people living with SCD in America, the report said. “Because of systemic racism, unconscious bias, and the stigma associated with the diagnosis, the disease brings with it a much broader burden.”

Dr. Osunkwo put it this way: “SCD is a disease that mostly affects Brown and Black people, and that gets layered into the whole discrimination issues that Black and Brown people face compounding the health burden from their disease.”

The report added that “the SCD community has developed a significant lack of trust in the health care system due to the nearly universal stigma and lack of belief in their reports of pain, a lack of trust that has been further reinforced by historical events, such as the Tuskegee experiment.”

The report highlighted research that finds that Blacks “are more likely to receive a lower quality of pain management than white patients and may be perceived as having drug-seeking behavior.”

The report also identified gaps in treatment, noting that “many SCD complications are not restricted to any one organ system, and the impact of the disease on [quality of life] can be profound but hard to define and compartmentalize.”

Dr. Osunkwo said medical professionals often fail to understand the full breadth of the disease. “There’s no particular look to SCD. When you have cancer, you come in, and you look like you’re sick because you’re bald. Everyone clues into that cancer look and knows it’s lethal, that you’re may likely die early. We don’t have that “look that generates empathy” for SCD, and people don’t understand the burden on those affected. They don’t understand or appreciate that SCD shortens your lifespan as well ... that people living with SCD die 3 decades earlier than their ethnically matched peers. Also, SCD is associated with a lot of pain, and pain and the treatment of pain with opioids makes people [health care providers] uncomfortable unless it’s cancer pain.”

She added: “People also assume that, if it’s not pain, it’s not SCD even though SCD can cause leg ulcers and blood clots and even affect the tonsils, or lead to a stroke. When a disease complexity is too difficult for providers to understand, they either avoid it or don’t do anything for the patient.”

Screening and surveillance for SCD and sickle cell trait is insufficient, the report said, and the potential cost of missed childhood cases is large. Detecting the condition at birth allows the implementation of appropriate comprehensive care and treatment to prevent early death from infections and strokes. As the authors noted, “tremendous strides have been made in the past few decades in the care of children with SCD, which have led to almost all children in high-income settings surviving to adulthood.” However, there remains gaps in care coordination and follow-up of babies screened at birth and even bigger gaps in translating these life span gains to adults particularly around the period of transition from pediatrics to adult care when there appears to be a spike in morbidity and mortality.

Dr_Microbe/Thinkstock

The report summarized current treatments for SCD and noted “an influx of pipeline products” after years of little progress and identifies “a need for targeted SCD therapies that address the underlying cause of the disease.”

While treatment recommendations exist, Dr. Osunkwo said, “the evidence for them is very poor and many SCD complications have no evidence-based guidelines for providers to follow. We need more research to provide high quality evidence to make guidelines for SCD treatment stronger and more robust.”

In its final section, the report offers a “strategic plan and blueprint for sickle cell disease action.” It offers several strategies to achieve the vision of “long healthy productive lives for those living with sickle cell disease and sickle cell trait”:

• Establish and fund a research agenda to inform effective programs and policies across the life span.
• Implement efforts to advance understanding of the full impact of sickle cell trait on individuals and society.
• Address barriers to accessing current and pipeline therapies for SCD.
• Improve SCD awareness and strengthen advocacy efforts.
• Increase the number of qualified health professionals providing SCD care.
• Strengthen the evidence base for interventions and disease management and implement widespread efforts to monitor the quality of SCD care.
• Establish organized systems of care assuring both clinical and nonclinical supportive services to all persons living with SCD.
• Establish a national system to collect and link data to characterize the burden of disease, outcomes, and the needs of those with SCD across the life span.

“Right now, the average lifespan for SCD is in the mid-40s to mid-50s,” Dr. Osunkwo said. “That’s a horrible statistic. Even if we just take up half of these recommendations, people will live longer with SCD, and they’ll be more productive and contribute more to society. If we value a cancer life the same as a sickle cell life, we’ll be halfway across the finish line. But the stigma of SCD being a Black and Brown problem is going to be the hardest to confront as it requires a systemic change in our culture as a country and a health care system.”

Still, she said, the commissioning of the report “shows that there is a desire to understand the issue in better detail and try to mitigate it.”

Dr. Osunkwo and Dr. McCormick had no relevant disclosures.

SOURCE: National Academies of Sciences, Engineering, and Medicine. Addressing Sickle Cell Disease: A Strategic Plan and Blueprint for Action. Washington, D.C.: National Academies Press, 2020.

The National Academies of Science, Engineering, and Medicine have just released a 522-page report, but it’s not the usual compilation of guidelines for treatment of a disease. Instead, the authors of “Addressing Sickle Cell Disease: A Strategic Plan and Blueprint for Action” argue in stark terms that the American society has colossally failed individuals living with sickle cell disease (SCD), who are mostly Black or Brown. A dramatic overhaul of the country’s medical and societal priorities is needed to turn things around to improve health and longevity among this rare disease population.

Courtesy Wikimedia Commons/Osaro Erhabor/Creative Commons License

The findings from the NASEM report are explicit: “There has been substantial success in increasing the survival of children with SCD, but this success had not been translated to similar success as they become adults.” One factor posited to contribute to the slow progress in the improvement of quality and quantity of life for adults living with this disease is the fact that “SCD is largely a disease of African Americans, and as such exists in a context of racial discrimination, health and other societal disparities, mistrust of the health care system, and the effects of poverty.” The report also cites the substantial evidence that those with SCD may receive poorer quality of care.

The report’s 14 authors were made up of an ad hoc committee formed at the request of the Department of Health & Human Services’ Office of Minority Health. The office asked NASEM to convene the committee to develop a strategic plan and blueprint for the United States and others regarding SCD.

The NASEM SCD committee members “realized that we can’t address the medical components of SCD if we don’t explore societal issues and why it’s been so hard to get good care for people with sickle cell disease,” hematologist and report coauthor Ifeyinwa (Ify) Osunkwo, MD, professor of medicine and pediatrics at Atrium Health and director of the Sickle Cell Disease Enterprise, Levine Cancer Institute, Charlotte, N.C., said in an interview. Dr. Osunkwo is also the medical editor of Hematology News.

“After almost a year of meetings and digging into the background and history of SCD care, we came out with very comprehensive summary of where we were and where we want to be,” she said. “The report provides short-, intermediate- and long-term recommendations and identifies which entity and organization should be responsible for implementing them.”

The report authors, led by pediatrician and committee chair Marie Clare McCormick, MD, of the Harvard School of Public Health, Boston, stated that about 100,000 people in the United States and millions worldwide live with SCD. The disease kills more than 700 people per year in the United States, and treatment costs an estimated $2 billion a year.

When judged by disability-adjusted life-years lost – a measurement of expected healthy years of life without an illness – the impact of SCD on individuals is estimated to be greater than a long list of other diseases such as Alzheimer’s disease, breast cancer, type 1 diabetes, and AIDS/HIV, the report noted.

“The health care needs of individuals living with SCD have been neglected by the U.S. and global health care systems, causing them and their families to suffer,” the report said. “Many of the complications that afflict individuals with SCD, particularly pain, are invisible. Pain is only diagnosed by self-reports, and in SCD there are few to no external indicators of the pain experience. Nevertheless, the pain can be excruciatingly severe and requires treatment with strong analgesics.”

There’s even more misery to the story of SCD, the report said, and Dr. Osunkwo agreed. “It’s not just about pain. These individuals suffer from multiple organ-system complications that are physical but also psychological and societal. They experience a lot of disparities in every aspect of their lives. You’re sick, so then you can’t get a job or health insurance, you can’t get Social Security benefits. You can’t get the type of health care you need nor can you access the other forms of support you need and often you are judged as a drug seeker for complaining of pain or repeatedly seeking acute care for unresolved pain.”

Multiple factors exacerbate the experience of people living with SCD in America, the report said. “Because of systemic racism, unconscious bias, and the stigma associated with the diagnosis, the disease brings with it a much broader burden.”

Dr. Osunkwo put it this way: “SCD is a disease that mostly affects Brown and Black people, and that gets layered into the whole discrimination issues that Black and Brown people face compounding the health burden from their disease.”

The report added that “the SCD community has developed a significant lack of trust in the health care system due to the nearly universal stigma and lack of belief in their reports of pain, a lack of trust that has been further reinforced by historical events, such as the Tuskegee experiment.”

The report highlighted research that finds that Blacks “are more likely to receive a lower quality of pain management than white patients and may be perceived as having drug-seeking behavior.”

The report also identified gaps in treatment, noting that “many SCD complications are not restricted to any one organ system, and the impact of the disease on [quality of life] can be profound but hard to define and compartmentalize.”

Dr. Osunkwo said medical professionals often fail to understand the full breadth of the disease. “There’s no particular look to SCD. When you have cancer, you come in, and you look like you’re sick because you’re bald. Everyone clues into that cancer look and knows it’s lethal, that you’re may likely die early. We don’t have that “look that generates empathy” for SCD, and people don’t understand the burden on those affected. They don’t understand or appreciate that SCD shortens your lifespan as well ... that people living with SCD die 3 decades earlier than their ethnically matched peers. Also, SCD is associated with a lot of pain, and pain and the treatment of pain with opioids makes people [health care providers] uncomfortable unless it’s cancer pain.”

She added: “People also assume that, if it’s not pain, it’s not SCD even though SCD can cause leg ulcers and blood clots and even affect the tonsils, or lead to a stroke. When a disease complexity is too difficult for providers to understand, they either avoid it or don’t do anything for the patient.”

Screening and surveillance for SCD and sickle cell trait is insufficient, the report said, and the potential cost of missed childhood cases is large. Detecting the condition at birth allows the implementation of appropriate comprehensive care and treatment to prevent early death from infections and strokes. As the authors noted, “tremendous strides have been made in the past few decades in the care of children with SCD, which have led to almost all children in high-income settings surviving to adulthood.” However, there remains gaps in care coordination and follow-up of babies screened at birth and even bigger gaps in translating these life span gains to adults particularly around the period of transition from pediatrics to adult care when there appears to be a spike in morbidity and mortality.

Dr_Microbe/Thinkstock

The report summarized current treatments for SCD and noted “an influx of pipeline products” after years of little progress and identifies “a need for targeted SCD therapies that address the underlying cause of the disease.”

While treatment recommendations exist, Dr. Osunkwo said, “the evidence for them is very poor and many SCD complications have no evidence-based guidelines for providers to follow. We need more research to provide high quality evidence to make guidelines for SCD treatment stronger and more robust.”

In its final section, the report offers a “strategic plan and blueprint for sickle cell disease action.” It offers several strategies to achieve the vision of “long healthy productive lives for those living with sickle cell disease and sickle cell trait”:

• Establish and fund a research agenda to inform effective programs and policies across the life span.
• Implement efforts to advance understanding of the full impact of sickle cell trait on individuals and society.
• Address barriers to accessing current and pipeline therapies for SCD.
• Improve SCD awareness and strengthen advocacy efforts.
• Increase the number of qualified health professionals providing SCD care.
• Strengthen the evidence base for interventions and disease management and implement widespread efforts to monitor the quality of SCD care.
• Establish organized systems of care assuring both clinical and nonclinical supportive services to all persons living with SCD.
• Establish a national system to collect and link data to characterize the burden of disease, outcomes, and the needs of those with SCD across the life span.

“Right now, the average lifespan for SCD is in the mid-40s to mid-50s,” Dr. Osunkwo said. “That’s a horrible statistic. Even if we just take up half of these recommendations, people will live longer with SCD, and they’ll be more productive and contribute more to society. If we value a cancer life the same as a sickle cell life, we’ll be halfway across the finish line. But the stigma of SCD being a Black and Brown problem is going to be the hardest to confront as it requires a systemic change in our culture as a country and a health care system.”

Still, she said, the commissioning of the report “shows that there is a desire to understand the issue in better detail and try to mitigate it.”

Dr. Osunkwo and Dr. McCormick had no relevant disclosures.

SOURCE: National Academies of Sciences, Engineering, and Medicine. Addressing Sickle Cell Disease: A Strategic Plan and Blueprint for Action. Washington, D.C.: National Academies Press, 2020.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

Oxidative stress-related genetic variants, in particular, the SOD2 Val16Ala polymorphism, may represent a simple and inexpensive alternative for identifying patients at risk of stroke, according to Igor F. Domingos of the Genetics Postgraduate Program, Federal University of Pernambuco, Recife, Brazil, and colleagues.

The researchers genotyped 499 unrelated adult patients with sickle cell anemia (SCA) for a variety of polymorphisms, along with alpha-thalassemia status and beta-globin gene haplotypes.

They found that SOD2 Val16Ala polymorphism was independently associated with risk of stroke (odds ratio, 1.98; 95% confidence interval, 1.18-3.32; P = .009) and with the long-term cumulative incidence of stroke (hazard ratio, 2.24; 95% CI, 1.3-3.9; P = .004).

A crucial limitation identified by the authors was the inability to replicate their results in a validation cohort. They suggested that there could have been genetic differences between the Brazilian population and the validation cohort of 231 patients followed at King’s College London for whom biological samples was available. They also suggested that patient treatment history between the two countries may be a factor.

“We believe that our study represents an alternative for understudied SCA populations with no access to TCD [transcranial Doppler ultrasound screening] and imaging exams, in which genetic modifiers may be a useful tool for predicting stroke in SCA,” the authors concluded.

The authors reported that they had no competing financial interests.

[email protected]

SOURCE: Domingos IF et al. J Neurol Sci. 2020 Apr 16; doi: 10.1016/j.jns.2020.116839.

Oxidative stress-related genetic variants, in particular, the SOD2 Val16Ala polymorphism, may represent a simple and inexpensive alternative for identifying patients at risk of stroke, according to Igor F. Domingos of the Genetics Postgraduate Program, Federal University of Pernambuco, Recife, Brazil, and colleagues.

The researchers genotyped 499 unrelated adult patients with sickle cell anemia (SCA) for a variety of polymorphisms, along with alpha-thalassemia status and beta-globin gene haplotypes.

They found that SOD2 Val16Ala polymorphism was independently associated with risk of stroke (odds ratio, 1.98; 95% confidence interval, 1.18-3.32; P = .009) and with the long-term cumulative incidence of stroke (hazard ratio, 2.24; 95% CI, 1.3-3.9; P = .004).

A crucial limitation identified by the authors was the inability to replicate their results in a validation cohort. They suggested that there could have been genetic differences between the Brazilian population and the validation cohort of 231 patients followed at King’s College London for whom biological samples was available. They also suggested that patient treatment history between the two countries may be a factor.

“We believe that our study represents an alternative for understudied SCA populations with no access to TCD [transcranial Doppler ultrasound screening] and imaging exams, in which genetic modifiers may be a useful tool for predicting stroke in SCA,” the authors concluded.

The authors reported that they had no competing financial interests.

[email protected]

SOURCE: Domingos IF et al. J Neurol Sci. 2020 Apr 16; doi: 10.1016/j.jns.2020.116839.

Oxidative stress-related genetic variants, in particular, the SOD2 Val16Ala polymorphism, may represent a simple and inexpensive alternative for identifying patients at risk of stroke, according to Igor F. Domingos of the Genetics Postgraduate Program, Federal University of Pernambuco, Recife, Brazil, and colleagues.

The researchers genotyped 499 unrelated adult patients with sickle cell anemia (SCA) for a variety of polymorphisms, along with alpha-thalassemia status and beta-globin gene haplotypes.

They found that SOD2 Val16Ala polymorphism was independently associated with risk of stroke (odds ratio, 1.98; 95% confidence interval, 1.18-3.32; P = .009) and with the long-term cumulative incidence of stroke (hazard ratio, 2.24; 95% CI, 1.3-3.9; P = .004).

A crucial limitation identified by the authors was the inability to replicate their results in a validation cohort. They suggested that there could have been genetic differences between the Brazilian population and the validation cohort of 231 patients followed at King’s College London for whom biological samples was available. They also suggested that patient treatment history between the two countries may be a factor.

“We believe that our study represents an alternative for understudied SCA populations with no access to TCD [transcranial Doppler ultrasound screening] and imaging exams, in which genetic modifiers may be a useful tool for predicting stroke in SCA,” the authors concluded.

The authors reported that they had no competing financial interests.

[email protected]

SOURCE: Domingos IF et al. J Neurol Sci. 2020 Apr 16; doi: 10.1016/j.jns.2020.116839.