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NHLBI commits to a sickle cell cure
“We have new exigency and intensity of effort to enable curative strategies for sickle cell disease to move forward,” said W. Keith Hoots, MD, the director of the division of blood diseases at NHLBI.
The key word in the cure effort is partnership – whether it’s among federal agencies, with public and private organizations, or with patients and families.
“Developmental strategies are built on partnerships to enhance care and accelerate cure for sickle cell disease in the U.S. and worldwide,” Dr. Hoots said at the 12th annual symposium of the Foundation for Sickle Cell Disease Research in Washington.
The reach also extends internationally. Supporting research in sub-Saharan Africa has promised to accelerate the clinical trial process by bringing advanced research capabilities to a region with a very high per capita rate of SCD. While in the United States, infrastructure is being built for a future research network, with the goal of developing a secure database of shared elements that harmonize and unite existing data.
Future cohort studies, enhanced newborn screening, and higher uptake of hydroxyurea will all be supported as part of this effort, Dr. Hoots said.
In the United States, patients can participate in a meaningful way as citizen-scientists, as new technology makes it possible to crowdsource high-quality data collection securely.
And including both community organizations and primary care providers in the “circle of partners” means not only that advances are brought out to patients expeditiously but also that the voices of patients and families have a clear channel back to researchers and policy makers through formal patient engagement and lay participation at all levels, Dr. Hoots said.
“The number of presently interested partners may surprise you,” Dr. Hoots said.
This multifaceted approach allows for “multiple shots on goal, with the acceptance that there could potentially be some failures,” Dr. Hoots said. Keeping all players better connected, though, should allow efforts to be redirected when needed, with a particular focus on accelerating work toward genetic therapies for SCD.
Perhaps the flagship effort is the Cure Sickle Cell Disease Initiative, a new partnership focused on accelerating cure-focused SCD research by filling in gaps left in the network of other funding strategies.
NHLBI named Edward J. Benz Jr., MD, the president and CEO emeritus of Boston’s Dana-Farber Cancer Institute, as the executive director and the Emmes Corporation, a contract research organization with expertise in clinical trials, as the coordinating center.
Traveling the last mile
New strategies also need to focus on how to boost uptake of such currently available best practices in SCD treatment as hydroxyurea use. To that end, Dr. Hoots said, NHLBI is drawing on implementation science, a discipline that, in a medical setting, can help solve such “last-mile” problems as bringing best practices in SCD treatment to patients.
In clinical practice, this might look like solving transportation issues for family members so that appointments aren’t missed and hydroxyurea prescriptions are filled. For researchers, implementation science can help with thorny details of participant recruitment and retention.
Established in 2016, the Sickle Cell Disease Implementation Consortium comprises nine U.S. research centers and NHLBI, which are each seeking to recruit at least 300 participants with SCD, aged 15-45 years, to study effective identification of barriers to care, and the best means to overcome them.
However, Dr. Hoots said, NHLBI also will continue funding SCD research through the traditional investigator-initiated application process, in conjunction with “a suite of specialized programs that can support translational and clinical research in SCD.”
Some of the features rolling out within the Cure SCD Initiative are included in direct response to stakeholder feedback about pressing needs and top priorities. For example, an economic case needed to be made in order for insurance companies, public and private alike, to reimburse for genetic SCD treatments. This requires an understanding of the lifetime cost burden of SCD, as well as determining what the long-term follow-up of costs of gene therapy will be.
Patients, family members and those providing primary care for SCD patients all agreed that clinical trials should have endpoints that reflect meaningful outcomes for patients and should be designed with the input of both patients and providers.
When queried, sickle cell disease researchers expressed a need to identify common data elements in SCD research, and wished for a secure yet accessible national data warehouse for data from gene and cell therapy trials.
At present, there are three clinical trials of curative stem cell approaches for SCD registered with the Blood and Marrow Transplant Clinical Trials Network and several more early phase clinical trials underway, Dr. Hoots said. A primary focus is the use of autologous cells for genomic editing, gene therapy, and erythroid-specific vectors.
Genetic research
As an example of the new collaboration, research centers and biotechnology companies sent their cell and genetic therapy experts to an NIH-sponsored gathering in March 2017. By pooling expertise in this way, the group was able to “identify some unprecedented opportunities, as well as some necessary barriers to overcome,” he said. These players continue to collaborate in the ongoing clinical trials of novel – and potentially curative – SCD therapies.
The TOPMed (Trans-Omics for Precision Medicine) program is a key mechanism to support SCD-related genetic research. For example, Dr. Hoots said, TOPMed is being used in support of whole-genome sequencing in a longitudinal cohort of patients with SCD who receive transfusion care at four large centers in Brazil.
These renewed efforts, set against the backdrop of paradigm-shifting genetic therapies, represent new promise for a generation of individuals with SCD, Dr. Hoots said. “It takes all of us to address the SCD challenge.”
ASH initiatives
NHLBI isn’t alone in making SCD a priority. The American Society of Hematology also is putting a spotlight on the condition.
The ASH multifaceted sickle cell disease (SCD) initiative addresses the disease burden both within the United States and globally, said LaTasha Lee, PhD, senior manager of sickle cell disease policy and programs for ASH.
Speaking at the 12th annual symposium of the Foundation for Sickle Cell Disease Research, Dr. Lee said that four prongs make up the initiative: disease research, attention to global issues, a renewed focus on access to care in the United States, and work to develop ASH’s new SCD guidelines.
New guidelines on the management of acute and chronic complications of SCD are in the works, with an anticipated 2019 date for publication of five separate guidelines. Topics covered in the guidelines will include pain, cerebrovascular disease, cardiopulmonary and kidney disease, transfusion support, and stem cell transplantation.
“We have new exigency and intensity of effort to enable curative strategies for sickle cell disease to move forward,” said W. Keith Hoots, MD, the director of the division of blood diseases at NHLBI.
The key word in the cure effort is partnership – whether it’s among federal agencies, with public and private organizations, or with patients and families.
“Developmental strategies are built on partnerships to enhance care and accelerate cure for sickle cell disease in the U.S. and worldwide,” Dr. Hoots said at the 12th annual symposium of the Foundation for Sickle Cell Disease Research in Washington.
The reach also extends internationally. Supporting research in sub-Saharan Africa has promised to accelerate the clinical trial process by bringing advanced research capabilities to a region with a very high per capita rate of SCD. While in the United States, infrastructure is being built for a future research network, with the goal of developing a secure database of shared elements that harmonize and unite existing data.
Future cohort studies, enhanced newborn screening, and higher uptake of hydroxyurea will all be supported as part of this effort, Dr. Hoots said.
In the United States, patients can participate in a meaningful way as citizen-scientists, as new technology makes it possible to crowdsource high-quality data collection securely.
And including both community organizations and primary care providers in the “circle of partners” means not only that advances are brought out to patients expeditiously but also that the voices of patients and families have a clear channel back to researchers and policy makers through formal patient engagement and lay participation at all levels, Dr. Hoots said.
“The number of presently interested partners may surprise you,” Dr. Hoots said.
This multifaceted approach allows for “multiple shots on goal, with the acceptance that there could potentially be some failures,” Dr. Hoots said. Keeping all players better connected, though, should allow efforts to be redirected when needed, with a particular focus on accelerating work toward genetic therapies for SCD.
Perhaps the flagship effort is the Cure Sickle Cell Disease Initiative, a new partnership focused on accelerating cure-focused SCD research by filling in gaps left in the network of other funding strategies.
NHLBI named Edward J. Benz Jr., MD, the president and CEO emeritus of Boston’s Dana-Farber Cancer Institute, as the executive director and the Emmes Corporation, a contract research organization with expertise in clinical trials, as the coordinating center.
Traveling the last mile
New strategies also need to focus on how to boost uptake of such currently available best practices in SCD treatment as hydroxyurea use. To that end, Dr. Hoots said, NHLBI is drawing on implementation science, a discipline that, in a medical setting, can help solve such “last-mile” problems as bringing best practices in SCD treatment to patients.
In clinical practice, this might look like solving transportation issues for family members so that appointments aren’t missed and hydroxyurea prescriptions are filled. For researchers, implementation science can help with thorny details of participant recruitment and retention.
Established in 2016, the Sickle Cell Disease Implementation Consortium comprises nine U.S. research centers and NHLBI, which are each seeking to recruit at least 300 participants with SCD, aged 15-45 years, to study effective identification of barriers to care, and the best means to overcome them.
However, Dr. Hoots said, NHLBI also will continue funding SCD research through the traditional investigator-initiated application process, in conjunction with “a suite of specialized programs that can support translational and clinical research in SCD.”
Some of the features rolling out within the Cure SCD Initiative are included in direct response to stakeholder feedback about pressing needs and top priorities. For example, an economic case needed to be made in order for insurance companies, public and private alike, to reimburse for genetic SCD treatments. This requires an understanding of the lifetime cost burden of SCD, as well as determining what the long-term follow-up of costs of gene therapy will be.
Patients, family members and those providing primary care for SCD patients all agreed that clinical trials should have endpoints that reflect meaningful outcomes for patients and should be designed with the input of both patients and providers.
When queried, sickle cell disease researchers expressed a need to identify common data elements in SCD research, and wished for a secure yet accessible national data warehouse for data from gene and cell therapy trials.
At present, there are three clinical trials of curative stem cell approaches for SCD registered with the Blood and Marrow Transplant Clinical Trials Network and several more early phase clinical trials underway, Dr. Hoots said. A primary focus is the use of autologous cells for genomic editing, gene therapy, and erythroid-specific vectors.
Genetic research
As an example of the new collaboration, research centers and biotechnology companies sent their cell and genetic therapy experts to an NIH-sponsored gathering in March 2017. By pooling expertise in this way, the group was able to “identify some unprecedented opportunities, as well as some necessary barriers to overcome,” he said. These players continue to collaborate in the ongoing clinical trials of novel – and potentially curative – SCD therapies.
The TOPMed (Trans-Omics for Precision Medicine) program is a key mechanism to support SCD-related genetic research. For example, Dr. Hoots said, TOPMed is being used in support of whole-genome sequencing in a longitudinal cohort of patients with SCD who receive transfusion care at four large centers in Brazil.
These renewed efforts, set against the backdrop of paradigm-shifting genetic therapies, represent new promise for a generation of individuals with SCD, Dr. Hoots said. “It takes all of us to address the SCD challenge.”
ASH initiatives
NHLBI isn’t alone in making SCD a priority. The American Society of Hematology also is putting a spotlight on the condition.
The ASH multifaceted sickle cell disease (SCD) initiative addresses the disease burden both within the United States and globally, said LaTasha Lee, PhD, senior manager of sickle cell disease policy and programs for ASH.
Speaking at the 12th annual symposium of the Foundation for Sickle Cell Disease Research, Dr. Lee said that four prongs make up the initiative: disease research, attention to global issues, a renewed focus on access to care in the United States, and work to develop ASH’s new SCD guidelines.
New guidelines on the management of acute and chronic complications of SCD are in the works, with an anticipated 2019 date for publication of five separate guidelines. Topics covered in the guidelines will include pain, cerebrovascular disease, cardiopulmonary and kidney disease, transfusion support, and stem cell transplantation.
“We have new exigency and intensity of effort to enable curative strategies for sickle cell disease to move forward,” said W. Keith Hoots, MD, the director of the division of blood diseases at NHLBI.
The key word in the cure effort is partnership – whether it’s among federal agencies, with public and private organizations, or with patients and families.
“Developmental strategies are built on partnerships to enhance care and accelerate cure for sickle cell disease in the U.S. and worldwide,” Dr. Hoots said at the 12th annual symposium of the Foundation for Sickle Cell Disease Research in Washington.
The reach also extends internationally. Supporting research in sub-Saharan Africa has promised to accelerate the clinical trial process by bringing advanced research capabilities to a region with a very high per capita rate of SCD. While in the United States, infrastructure is being built for a future research network, with the goal of developing a secure database of shared elements that harmonize and unite existing data.
Future cohort studies, enhanced newborn screening, and higher uptake of hydroxyurea will all be supported as part of this effort, Dr. Hoots said.
In the United States, patients can participate in a meaningful way as citizen-scientists, as new technology makes it possible to crowdsource high-quality data collection securely.
And including both community organizations and primary care providers in the “circle of partners” means not only that advances are brought out to patients expeditiously but also that the voices of patients and families have a clear channel back to researchers and policy makers through formal patient engagement and lay participation at all levels, Dr. Hoots said.
“The number of presently interested partners may surprise you,” Dr. Hoots said.
This multifaceted approach allows for “multiple shots on goal, with the acceptance that there could potentially be some failures,” Dr. Hoots said. Keeping all players better connected, though, should allow efforts to be redirected when needed, with a particular focus on accelerating work toward genetic therapies for SCD.
Perhaps the flagship effort is the Cure Sickle Cell Disease Initiative, a new partnership focused on accelerating cure-focused SCD research by filling in gaps left in the network of other funding strategies.
NHLBI named Edward J. Benz Jr., MD, the president and CEO emeritus of Boston’s Dana-Farber Cancer Institute, as the executive director and the Emmes Corporation, a contract research organization with expertise in clinical trials, as the coordinating center.
Traveling the last mile
New strategies also need to focus on how to boost uptake of such currently available best practices in SCD treatment as hydroxyurea use. To that end, Dr. Hoots said, NHLBI is drawing on implementation science, a discipline that, in a medical setting, can help solve such “last-mile” problems as bringing best practices in SCD treatment to patients.
In clinical practice, this might look like solving transportation issues for family members so that appointments aren’t missed and hydroxyurea prescriptions are filled. For researchers, implementation science can help with thorny details of participant recruitment and retention.
Established in 2016, the Sickle Cell Disease Implementation Consortium comprises nine U.S. research centers and NHLBI, which are each seeking to recruit at least 300 participants with SCD, aged 15-45 years, to study effective identification of barriers to care, and the best means to overcome them.
However, Dr. Hoots said, NHLBI also will continue funding SCD research through the traditional investigator-initiated application process, in conjunction with “a suite of specialized programs that can support translational and clinical research in SCD.”
Some of the features rolling out within the Cure SCD Initiative are included in direct response to stakeholder feedback about pressing needs and top priorities. For example, an economic case needed to be made in order for insurance companies, public and private alike, to reimburse for genetic SCD treatments. This requires an understanding of the lifetime cost burden of SCD, as well as determining what the long-term follow-up of costs of gene therapy will be.
Patients, family members and those providing primary care for SCD patients all agreed that clinical trials should have endpoints that reflect meaningful outcomes for patients and should be designed with the input of both patients and providers.
When queried, sickle cell disease researchers expressed a need to identify common data elements in SCD research, and wished for a secure yet accessible national data warehouse for data from gene and cell therapy trials.
At present, there are three clinical trials of curative stem cell approaches for SCD registered with the Blood and Marrow Transplant Clinical Trials Network and several more early phase clinical trials underway, Dr. Hoots said. A primary focus is the use of autologous cells for genomic editing, gene therapy, and erythroid-specific vectors.
Genetic research
As an example of the new collaboration, research centers and biotechnology companies sent their cell and genetic therapy experts to an NIH-sponsored gathering in March 2017. By pooling expertise in this way, the group was able to “identify some unprecedented opportunities, as well as some necessary barriers to overcome,” he said. These players continue to collaborate in the ongoing clinical trials of novel – and potentially curative – SCD therapies.
The TOPMed (Trans-Omics for Precision Medicine) program is a key mechanism to support SCD-related genetic research. For example, Dr. Hoots said, TOPMed is being used in support of whole-genome sequencing in a longitudinal cohort of patients with SCD who receive transfusion care at four large centers in Brazil.
These renewed efforts, set against the backdrop of paradigm-shifting genetic therapies, represent new promise for a generation of individuals with SCD, Dr. Hoots said. “It takes all of us to address the SCD challenge.”
ASH initiatives
NHLBI isn’t alone in making SCD a priority. The American Society of Hematology also is putting a spotlight on the condition.
The ASH multifaceted sickle cell disease (SCD) initiative addresses the disease burden both within the United States and globally, said LaTasha Lee, PhD, senior manager of sickle cell disease policy and programs for ASH.
Speaking at the 12th annual symposium of the Foundation for Sickle Cell Disease Research, Dr. Lee said that four prongs make up the initiative: disease research, attention to global issues, a renewed focus on access to care in the United States, and work to develop ASH’s new SCD guidelines.
New guidelines on the management of acute and chronic complications of SCD are in the works, with an anticipated 2019 date for publication of five separate guidelines. Topics covered in the guidelines will include pain, cerebrovascular disease, cardiopulmonary and kidney disease, transfusion support, and stem cell transplantation.
Integrated pain program reduced LOS for sickle cell patients
WASHINGTON – Pediatric patients who received interdisciplinary outpatient care for sickle cell disease–related chronic pain experienced a reduction in average length of stay for pain-related hospitalizations, according to an exploratory analysis of patient outcomes at a single center.
Experiences at Children’s Mercy Hospital in Kansas City, Mo., have added to the body of evidence supporting integrative care for sickle cell disease (SCD) pain, Derrick L. Goubeaux, DO, said during an interview at the annual symposium of the Foundation for Sickle Cell Disease Research.
With time, chronic pain can become an overlay on pain from vasoocclusive crises as patients with SCD age, shifting the way that patients and providers think about pain, said Dr. Goubeaux, a pediatric hematology/oncology fellow at Children’s Mercy Hospital in Kansas City.
Using a collaborative approach that pulls in psychologists, social workers, and pain management specialists, the hospital’s multidisciplinary Sickle Cell Integrated Pain Program (SCIPP) seeks to optimize pain control by adding nonpharmacologic measures to medications, he said.
Dr. Goubeaux and his colleagues conducted a retrospective chart review that looked at individuals who received care from, or were referred to, the institution’s SCD program. Included in the study were patients who received care for SCD for at least 2 years before their referral to the SCIPP clinic, so that investigators could compare care for those patients before and after SCIPP clinic integration. The study also included patients who had not yet been integrated into SCIPP clinic care, for comparison.
Though the seven patients who were integrated into the SCIPP clinic did not have fewer hospitalizations than the five who were not referred, average length of stay (LOS) for the SCIPP patients dropped from 11 days to 8 days. Mean LOS also decreased for the non-SCIPP patients, from 7.4 to 5.8 days. The number of admissions per month for both groups increased over the study period, from a mean of 0.41 to 0.84 admissions per month for SCIPP patients, and from 0.27 to 0.43 for non-SCIPP patients.
The patients, who ranged in age from 138 to 253 months, mostly had HbSS SCD, but HbSbeta0, HbSD, and HbSC patients were also included. Four patients in the SCIPP group and two of the non-SCIPP patients were taking hydroxyurea.
Noting that data collection is still in the early stages, Dr. Goubeaux and his collaborators observed that “the LOS has shortened by 3 days in the integrated group, compared to 1.6 days in the [non-SCIPP] group.” They are currently also investigating whether costs per admission and admission-associated opioid use differs for patients integrated into the SCIPP clinic.
Aside from the small number of patients studied, Dr. Goubeaux and his colleagues acknowledged that even non-SCIPP patients are likely to have had pain management and psychology consultations during their inpatient stays – and these consults are conducted by SCIPP-associated providers.
Dr. Goubeaux reported no relevant disclosures or outside sources of funding.
WASHINGTON – Pediatric patients who received interdisciplinary outpatient care for sickle cell disease–related chronic pain experienced a reduction in average length of stay for pain-related hospitalizations, according to an exploratory analysis of patient outcomes at a single center.
Experiences at Children’s Mercy Hospital in Kansas City, Mo., have added to the body of evidence supporting integrative care for sickle cell disease (SCD) pain, Derrick L. Goubeaux, DO, said during an interview at the annual symposium of the Foundation for Sickle Cell Disease Research.
With time, chronic pain can become an overlay on pain from vasoocclusive crises as patients with SCD age, shifting the way that patients and providers think about pain, said Dr. Goubeaux, a pediatric hematology/oncology fellow at Children’s Mercy Hospital in Kansas City.
Using a collaborative approach that pulls in psychologists, social workers, and pain management specialists, the hospital’s multidisciplinary Sickle Cell Integrated Pain Program (SCIPP) seeks to optimize pain control by adding nonpharmacologic measures to medications, he said.
Dr. Goubeaux and his colleagues conducted a retrospective chart review that looked at individuals who received care from, or were referred to, the institution’s SCD program. Included in the study were patients who received care for SCD for at least 2 years before their referral to the SCIPP clinic, so that investigators could compare care for those patients before and after SCIPP clinic integration. The study also included patients who had not yet been integrated into SCIPP clinic care, for comparison.
Though the seven patients who were integrated into the SCIPP clinic did not have fewer hospitalizations than the five who were not referred, average length of stay (LOS) for the SCIPP patients dropped from 11 days to 8 days. Mean LOS also decreased for the non-SCIPP patients, from 7.4 to 5.8 days. The number of admissions per month for both groups increased over the study period, from a mean of 0.41 to 0.84 admissions per month for SCIPP patients, and from 0.27 to 0.43 for non-SCIPP patients.
The patients, who ranged in age from 138 to 253 months, mostly had HbSS SCD, but HbSbeta0, HbSD, and HbSC patients were also included. Four patients in the SCIPP group and two of the non-SCIPP patients were taking hydroxyurea.
Noting that data collection is still in the early stages, Dr. Goubeaux and his collaborators observed that “the LOS has shortened by 3 days in the integrated group, compared to 1.6 days in the [non-SCIPP] group.” They are currently also investigating whether costs per admission and admission-associated opioid use differs for patients integrated into the SCIPP clinic.
Aside from the small number of patients studied, Dr. Goubeaux and his colleagues acknowledged that even non-SCIPP patients are likely to have had pain management and psychology consultations during their inpatient stays – and these consults are conducted by SCIPP-associated providers.
Dr. Goubeaux reported no relevant disclosures or outside sources of funding.
WASHINGTON – Pediatric patients who received interdisciplinary outpatient care for sickle cell disease–related chronic pain experienced a reduction in average length of stay for pain-related hospitalizations, according to an exploratory analysis of patient outcomes at a single center.
Experiences at Children’s Mercy Hospital in Kansas City, Mo., have added to the body of evidence supporting integrative care for sickle cell disease (SCD) pain, Derrick L. Goubeaux, DO, said during an interview at the annual symposium of the Foundation for Sickle Cell Disease Research.
With time, chronic pain can become an overlay on pain from vasoocclusive crises as patients with SCD age, shifting the way that patients and providers think about pain, said Dr. Goubeaux, a pediatric hematology/oncology fellow at Children’s Mercy Hospital in Kansas City.
Using a collaborative approach that pulls in psychologists, social workers, and pain management specialists, the hospital’s multidisciplinary Sickle Cell Integrated Pain Program (SCIPP) seeks to optimize pain control by adding nonpharmacologic measures to medications, he said.
Dr. Goubeaux and his colleagues conducted a retrospective chart review that looked at individuals who received care from, or were referred to, the institution’s SCD program. Included in the study were patients who received care for SCD for at least 2 years before their referral to the SCIPP clinic, so that investigators could compare care for those patients before and after SCIPP clinic integration. The study also included patients who had not yet been integrated into SCIPP clinic care, for comparison.
Though the seven patients who were integrated into the SCIPP clinic did not have fewer hospitalizations than the five who were not referred, average length of stay (LOS) for the SCIPP patients dropped from 11 days to 8 days. Mean LOS also decreased for the non-SCIPP patients, from 7.4 to 5.8 days. The number of admissions per month for both groups increased over the study period, from a mean of 0.41 to 0.84 admissions per month for SCIPP patients, and from 0.27 to 0.43 for non-SCIPP patients.
The patients, who ranged in age from 138 to 253 months, mostly had HbSS SCD, but HbSbeta0, HbSD, and HbSC patients were also included. Four patients in the SCIPP group and two of the non-SCIPP patients were taking hydroxyurea.
Noting that data collection is still in the early stages, Dr. Goubeaux and his collaborators observed that “the LOS has shortened by 3 days in the integrated group, compared to 1.6 days in the [non-SCIPP] group.” They are currently also investigating whether costs per admission and admission-associated opioid use differs for patients integrated into the SCIPP clinic.
Aside from the small number of patients studied, Dr. Goubeaux and his colleagues acknowledged that even non-SCIPP patients are likely to have had pain management and psychology consultations during their inpatient stays – and these consults are conducted by SCIPP-associated providers.
Dr. Goubeaux reported no relevant disclosures or outside sources of funding.
REPORTING FROM FSCDR 2018
Key clinical point:
Major finding: Mean length of stay dropped from 11 days to 8 days after patients were referred to a multidisciplinary care clinic.
Study details: A retrospective chart review of 12 pediatric patients with chronic sickle cell disease-related pain.
Disclosures: The authors reported no conflicts of interest or outside sources of funding.
For men with SCD and priapism, hypoxia may prompt RBC adhesion
WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.
In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.
When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.
The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.
The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.
Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.
Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.
However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).
When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).
Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.
When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).
Though numbers were small, RBCs from patients with reported priapism and hemoglobin desaturation in vivo showed increased hypoxia enhanced adhesion in vitro (P = .013), Ms. Quinn said. These was no significant difference between adhesion in normoxic and hypoxic conditions for the patients without priapism.
Future directions of work with the biochip include prospective identification of desaturation events and better characterization of nocturnal symptoms, Ms. Quinn said. The investigators also plan to see whether treatment with supplemental oxygen affects RBC adhesion.
The research was supported by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.
In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.
When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.
The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.
The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.
Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.
Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.
However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).
When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).
Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.
When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).
Though numbers were small, RBCs from patients with reported priapism and hemoglobin desaturation in vivo showed increased hypoxia enhanced adhesion in vitro (P = .013), Ms. Quinn said. These was no significant difference between adhesion in normoxic and hypoxic conditions for the patients without priapism.
Future directions of work with the biochip include prospective identification of desaturation events and better characterization of nocturnal symptoms, Ms. Quinn said. The investigators also plan to see whether treatment with supplemental oxygen affects RBC adhesion.
The research was supported by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.
In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.
When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.
The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.
The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.
Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.
Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.
However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).
When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).
Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.
When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).
Though numbers were small, RBCs from patients with reported priapism and hemoglobin desaturation in vivo showed increased hypoxia enhanced adhesion in vitro (P = .013), Ms. Quinn said. These was no significant difference between adhesion in normoxic and hypoxic conditions for the patients without priapism.
Future directions of work with the biochip include prospective identification of desaturation events and better characterization of nocturnal symptoms, Ms. Quinn said. The investigators also plan to see whether treatment with supplemental oxygen affects RBC adhesion.
The research was supported by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
REPORTING FROM FSCDR 2018
Key clinical point: RBC adhesion was increased, but only in hypoxia, for men with sickle cell disease and priapism.
Major finding: Men who had desaturations and priapism had significantly higher RBC adhesion than those without priapism (P = .013).
Study details: An in vitro and in vivo study of 26 men with HbSS sickle cell disease, with and without priapism.
Disclosures: The study was funded by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
Hydroxyurea well tolerated in longitudinal European study
WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.
ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is slated to enroll 2,000 children and adults over the study period to assess the long-term safety and efficacy of hydroxyurea (HU) as a treatment for SCD.
“Hydroxyurea is still underused in sickle cell disease” both in Europe and the United States, said Bernard Dauvergne, PharmD, executive director of Addmedica, which markets hydroxyurea as Siklos. In part, fears about toxicity and side effects contribute to this underuse, Dr. Dauvergne said at a top abstracts session of the annual meeting of the Foundation for Sickle Cell Disease Research.
ESCORT-HU was designed as a purely observational, noninterventional study of patients treated with HU. It was initiated as part of the European Medicines Agency risk management plan, conceived at the time of the drug’s approval for SCD, explained Dr. Dauvergne.
“This prospective cohort study could enable the identification of delayed rare adverse events in real life, occurring in between 1 in 10,000 and 1 in 1,000 patients,” Dr. Dauvergne said. However, “no new safety information has been detected ... and no secondary cancer has been reported.”
At the last data analysis cutpoint of June 2017, 1,921 patients had been enrolled. Patients have come from 63 centers in France, Germany, Greece, and Italy, Dr. Dauvergne reported.
Of the 1,829 patients with data available for analysis, 804 were under the age of 18. The pediatric patients were a mean 9 years of age, and the adult patients were a mean 33 years old at enrollment. Most enrollees (84%) have the HbSS genotype.
At baseline, the pediatric patients were dosed at a mean 17.2 mg/kg per day of HU; for adult patients, the figure was 15.54 mg/kg per day. More than one-third (35.4%) of pediatric patients had been on HU at the time of study enrollment, for a mean of 4.5 years. In contrast, more than half (60.4%) of adults had been taking hydroxyurea for a mean of 6.25 years at enrollment.
The 1,002 adult patients with recently reported safety data were on a mean HU dose of 20.2 mg/kg per day. About 40% of adults reported at least one adverse event (AE), and a total of 334 AEs in 16.3% of adult patients were judged to be related to HU.
Skin and subcutaneous tissue reactions occurred in about 1 in 10 patients, with 153 reported incidences of skin dryness, skin reactions, alopecia, or changes in skin pigmentation. The next most common adverse events were blood and lymphatic system disorders, mostly neutropenia or thrombocytopenia, occurring in 9.6% of patients.
Discontinuation rates have been low, with an overall dropout rate of 3.8%.
The ESCORT-HU data “confirm that HU is an efficient and well-tolerated drug in both children and adults,” Dr. Dauvergne said. Over the short term, adverse events are related to the expected dose dependent myelosuppression that’s key to the drug’s mechanism of action. This makes sense given the narrow therapeutic index, with a tight range between an efficacious dose and a cytotoxic one, he said. “And the lower the [patient] weight is, the more sensitive the dose variations become,” Dr. Dauvergne said.
Being flexible about fine-tuning doses is key to finding the balance between tolerability and efficacy, “and consequently, for compliance,” he said.
Data collection for the study will end in 2018, with safety and efficacy data expected in 2019.
WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.
ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is slated to enroll 2,000 children and adults over the study period to assess the long-term safety and efficacy of hydroxyurea (HU) as a treatment for SCD.
“Hydroxyurea is still underused in sickle cell disease” both in Europe and the United States, said Bernard Dauvergne, PharmD, executive director of Addmedica, which markets hydroxyurea as Siklos. In part, fears about toxicity and side effects contribute to this underuse, Dr. Dauvergne said at a top abstracts session of the annual meeting of the Foundation for Sickle Cell Disease Research.
ESCORT-HU was designed as a purely observational, noninterventional study of patients treated with HU. It was initiated as part of the European Medicines Agency risk management plan, conceived at the time of the drug’s approval for SCD, explained Dr. Dauvergne.
“This prospective cohort study could enable the identification of delayed rare adverse events in real life, occurring in between 1 in 10,000 and 1 in 1,000 patients,” Dr. Dauvergne said. However, “no new safety information has been detected ... and no secondary cancer has been reported.”
At the last data analysis cutpoint of June 2017, 1,921 patients had been enrolled. Patients have come from 63 centers in France, Germany, Greece, and Italy, Dr. Dauvergne reported.
Of the 1,829 patients with data available for analysis, 804 were under the age of 18. The pediatric patients were a mean 9 years of age, and the adult patients were a mean 33 years old at enrollment. Most enrollees (84%) have the HbSS genotype.
At baseline, the pediatric patients were dosed at a mean 17.2 mg/kg per day of HU; for adult patients, the figure was 15.54 mg/kg per day. More than one-third (35.4%) of pediatric patients had been on HU at the time of study enrollment, for a mean of 4.5 years. In contrast, more than half (60.4%) of adults had been taking hydroxyurea for a mean of 6.25 years at enrollment.
The 1,002 adult patients with recently reported safety data were on a mean HU dose of 20.2 mg/kg per day. About 40% of adults reported at least one adverse event (AE), and a total of 334 AEs in 16.3% of adult patients were judged to be related to HU.
Skin and subcutaneous tissue reactions occurred in about 1 in 10 patients, with 153 reported incidences of skin dryness, skin reactions, alopecia, or changes in skin pigmentation. The next most common adverse events were blood and lymphatic system disorders, mostly neutropenia or thrombocytopenia, occurring in 9.6% of patients.
Discontinuation rates have been low, with an overall dropout rate of 3.8%.
The ESCORT-HU data “confirm that HU is an efficient and well-tolerated drug in both children and adults,” Dr. Dauvergne said. Over the short term, adverse events are related to the expected dose dependent myelosuppression that’s key to the drug’s mechanism of action. This makes sense given the narrow therapeutic index, with a tight range between an efficacious dose and a cytotoxic one, he said. “And the lower the [patient] weight is, the more sensitive the dose variations become,” Dr. Dauvergne said.
Being flexible about fine-tuning doses is key to finding the balance between tolerability and efficacy, “and consequently, for compliance,” he said.
Data collection for the study will end in 2018, with safety and efficacy data expected in 2019.
WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.
ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is slated to enroll 2,000 children and adults over the study period to assess the long-term safety and efficacy of hydroxyurea (HU) as a treatment for SCD.
“Hydroxyurea is still underused in sickle cell disease” both in Europe and the United States, said Bernard Dauvergne, PharmD, executive director of Addmedica, which markets hydroxyurea as Siklos. In part, fears about toxicity and side effects contribute to this underuse, Dr. Dauvergne said at a top abstracts session of the annual meeting of the Foundation for Sickle Cell Disease Research.
ESCORT-HU was designed as a purely observational, noninterventional study of patients treated with HU. It was initiated as part of the European Medicines Agency risk management plan, conceived at the time of the drug’s approval for SCD, explained Dr. Dauvergne.
“This prospective cohort study could enable the identification of delayed rare adverse events in real life, occurring in between 1 in 10,000 and 1 in 1,000 patients,” Dr. Dauvergne said. However, “no new safety information has been detected ... and no secondary cancer has been reported.”
At the last data analysis cutpoint of June 2017, 1,921 patients had been enrolled. Patients have come from 63 centers in France, Germany, Greece, and Italy, Dr. Dauvergne reported.
Of the 1,829 patients with data available for analysis, 804 were under the age of 18. The pediatric patients were a mean 9 years of age, and the adult patients were a mean 33 years old at enrollment. Most enrollees (84%) have the HbSS genotype.
At baseline, the pediatric patients were dosed at a mean 17.2 mg/kg per day of HU; for adult patients, the figure was 15.54 mg/kg per day. More than one-third (35.4%) of pediatric patients had been on HU at the time of study enrollment, for a mean of 4.5 years. In contrast, more than half (60.4%) of adults had been taking hydroxyurea for a mean of 6.25 years at enrollment.
The 1,002 adult patients with recently reported safety data were on a mean HU dose of 20.2 mg/kg per day. About 40% of adults reported at least one adverse event (AE), and a total of 334 AEs in 16.3% of adult patients were judged to be related to HU.
Skin and subcutaneous tissue reactions occurred in about 1 in 10 patients, with 153 reported incidences of skin dryness, skin reactions, alopecia, or changes in skin pigmentation. The next most common adverse events were blood and lymphatic system disorders, mostly neutropenia or thrombocytopenia, occurring in 9.6% of patients.
Discontinuation rates have been low, with an overall dropout rate of 3.8%.
The ESCORT-HU data “confirm that HU is an efficient and well-tolerated drug in both children and adults,” Dr. Dauvergne said. Over the short term, adverse events are related to the expected dose dependent myelosuppression that’s key to the drug’s mechanism of action. This makes sense given the narrow therapeutic index, with a tight range between an efficacious dose and a cytotoxic one, he said. “And the lower the [patient] weight is, the more sensitive the dose variations become,” Dr. Dauvergne said.
Being flexible about fine-tuning doses is key to finding the balance between tolerability and efficacy, “and consequently, for compliance,” he said.
Data collection for the study will end in 2018, with safety and efficacy data expected in 2019.
REPORTING FROM FSCDR 2018
Key clinical point:
Major finding: Of adult participants, 16.9% have experienced hydroxyurea-related adverse events.
Study details: Observational 10-year study of 2,000 adults and children with SCD who were taking hydroxyurea.
Disclosures: The study was sponsored by Addmedica, which markets hydroxyurea as Siklos. Dr. Dauvergne is employed by Addmedica.
Source: Dauvergne B et al. FSCDR 2018, presentation JSCDH-D-18-00052.
Voxelotor cut transfusions in compassionate use sickle cell cohort
WASHINGTON – An investigational drug for sickle cell disease (SCD) boosted hemoglobin levels while reducing hospitalizations and transfusion needs by approximately two-thirds in a small cohort of severely affected patients.
Lanetta Bronté, MD, who presented the findings at the annual meeting of the Foundation for Sickle Cell Disease Research, reviewed the FDA’s requirements for allowing expanded access to an investigational drug. The key point, she said, is that expanded access may be granted “for treatment of patients with serious or immediately life-threatening diseases or conditions that lack therapeutic alternatives.” And, she said, the potential for benefit should outweigh potential risk of taking the investigational drug.
Current treatments don’t really address serious disease-related complications for patients with advanced SCD, she said. Furthermore, these patients will often be excluded from clinical trials of new SCD therapies.
Voxelotor is a novel small molecule that stabilizes the sickle hemoglobin molecule as a monomer in its high oxygen state. Thus, polymerization of the hemoglobin molecules is inhibited, which decreases the amount of red blood cell damage. Other beneficial effects of voxelotor include improved rheology and reduced hemolysis, as well as a boost to the oxygen-carrying capacity of the sickle hemoglobin molecules, Dr. Bronté explained.
For the seven patients in Dr. Bronté’s clinic who were granted expanded access to voxelator, the disease burden of their end-stage SCD was heavy. All participants had iron overload, five were receiving frequent transfusions, two required chronic oxygen supplementation, and four had severe fatigue. One patient had end-stage renal disease, and another had experienced multiple organ failure and prolonged hospitalizations.
None of the patients qualified for participation in ongoing clinical trials of voxelotor, said Dr. Bronté, who is president of the Foundation for Sickle Cell Disease Research. She also maintains a private practice in Hollywood, Fla.
The four women and three men, aged 22-67 years, were treated with voxelotor for a range of 6-17 months under the FDA’s Expanded Access Program. All patients saw rapid increases in serum hemoglobin, with increases of at least 1 g/dL in five of the seven. Across the participants, increases ranged from 0.5-5.4 g/dL at 24 weeks, up from baseline values of 5.2-7.8 g/dL.
One marker of clinical efficacy that Dr. Bronté and her coauthors examined was the number of hospitalizations for pain from vaso-occlusive crises (VOCs). In the 24 weeks before beginning voxelotor, participants had a summed total of 28 hospitalizations. In the first 24 weeks of treatment, there were a total of nine VOC-related hospitalizations among the participants, a 67% decrease.
The total number of red blood cell transfusions required by the study population declined by a similar proportion, from 33 during the 24 weeks before voxelotor treatment to 13 during the first 24 weeks of treatment, a decrease of 60%.
Individual patients saw improvements related to some of their most troublesome SCD complications, Dr. Bronté reported. All four patients whose oxygen saturation levels had been below 95% on room air saw oxygen saturations improve to 98%-99% on voxelotor. The two patients who had moderate or moderately severe depression, as assessed by the Patient Health Questionnaire 9-item, had minimal or no depression on retest after 24 weeks of voxelotor treatment.
Voxelotor was generally well tolerated at a 900-mg once-daily oral dose. One patient developed grade 2 diarrhea after increasing the dose to 1,500 mg, but symptoms resolved after returning to the 900-mg dose. Another patient had transient mild diarrhea on 900 mg of voxelotor; the symptoms resolved without changing or stopping the drug, Dr. Bronté said. There were no serious treatment-related adverse events.
Among this seriously ill population, two patients died after beginning voxelotor treatment, but both deaths were judged to be unrelated to the treatment. Dr. Bronté reported that the two deceased patients, one of whom was on voxelotor for 16 months and the other for 7 months, did experience reduced transfusion needs and reduced VOC-related hospitalizations while on the drug, experiences that were similar to the surviving members of the cohort.
“Voxelotor administered via compassionate use demonstrated large improvements in anemia and hemolysis, including in patients with lower baseline hemoglobin than studied in clinical trials to date,” Dr. Bronté said.
Taken together with clinical improvements and improved patient-focused outcomes among a severely affected population, “these data … support ongoing investigation in controlled clinical trials to confirm the benefits of voxelotor in a broad range of patients with SCD,” she said.
The study was supported by Global Blood Therapeutics, the manufacturer of voxelotor. Dr. Bronté reported having no other conflicts of interest.
WASHINGTON – An investigational drug for sickle cell disease (SCD) boosted hemoglobin levels while reducing hospitalizations and transfusion needs by approximately two-thirds in a small cohort of severely affected patients.
Lanetta Bronté, MD, who presented the findings at the annual meeting of the Foundation for Sickle Cell Disease Research, reviewed the FDA’s requirements for allowing expanded access to an investigational drug. The key point, she said, is that expanded access may be granted “for treatment of patients with serious or immediately life-threatening diseases or conditions that lack therapeutic alternatives.” And, she said, the potential for benefit should outweigh potential risk of taking the investigational drug.
Current treatments don’t really address serious disease-related complications for patients with advanced SCD, she said. Furthermore, these patients will often be excluded from clinical trials of new SCD therapies.
Voxelotor is a novel small molecule that stabilizes the sickle hemoglobin molecule as a monomer in its high oxygen state. Thus, polymerization of the hemoglobin molecules is inhibited, which decreases the amount of red blood cell damage. Other beneficial effects of voxelotor include improved rheology and reduced hemolysis, as well as a boost to the oxygen-carrying capacity of the sickle hemoglobin molecules, Dr. Bronté explained.
For the seven patients in Dr. Bronté’s clinic who were granted expanded access to voxelator, the disease burden of their end-stage SCD was heavy. All participants had iron overload, five were receiving frequent transfusions, two required chronic oxygen supplementation, and four had severe fatigue. One patient had end-stage renal disease, and another had experienced multiple organ failure and prolonged hospitalizations.
None of the patients qualified for participation in ongoing clinical trials of voxelotor, said Dr. Bronté, who is president of the Foundation for Sickle Cell Disease Research. She also maintains a private practice in Hollywood, Fla.
The four women and three men, aged 22-67 years, were treated with voxelotor for a range of 6-17 months under the FDA’s Expanded Access Program. All patients saw rapid increases in serum hemoglobin, with increases of at least 1 g/dL in five of the seven. Across the participants, increases ranged from 0.5-5.4 g/dL at 24 weeks, up from baseline values of 5.2-7.8 g/dL.
One marker of clinical efficacy that Dr. Bronté and her coauthors examined was the number of hospitalizations for pain from vaso-occlusive crises (VOCs). In the 24 weeks before beginning voxelotor, participants had a summed total of 28 hospitalizations. In the first 24 weeks of treatment, there were a total of nine VOC-related hospitalizations among the participants, a 67% decrease.
The total number of red blood cell transfusions required by the study population declined by a similar proportion, from 33 during the 24 weeks before voxelotor treatment to 13 during the first 24 weeks of treatment, a decrease of 60%.
Individual patients saw improvements related to some of their most troublesome SCD complications, Dr. Bronté reported. All four patients whose oxygen saturation levels had been below 95% on room air saw oxygen saturations improve to 98%-99% on voxelotor. The two patients who had moderate or moderately severe depression, as assessed by the Patient Health Questionnaire 9-item, had minimal or no depression on retest after 24 weeks of voxelotor treatment.
Voxelotor was generally well tolerated at a 900-mg once-daily oral dose. One patient developed grade 2 diarrhea after increasing the dose to 1,500 mg, but symptoms resolved after returning to the 900-mg dose. Another patient had transient mild diarrhea on 900 mg of voxelotor; the symptoms resolved without changing or stopping the drug, Dr. Bronté said. There were no serious treatment-related adverse events.
Among this seriously ill population, two patients died after beginning voxelotor treatment, but both deaths were judged to be unrelated to the treatment. Dr. Bronté reported that the two deceased patients, one of whom was on voxelotor for 16 months and the other for 7 months, did experience reduced transfusion needs and reduced VOC-related hospitalizations while on the drug, experiences that were similar to the surviving members of the cohort.
“Voxelotor administered via compassionate use demonstrated large improvements in anemia and hemolysis, including in patients with lower baseline hemoglobin than studied in clinical trials to date,” Dr. Bronté said.
Taken together with clinical improvements and improved patient-focused outcomes among a severely affected population, “these data … support ongoing investigation in controlled clinical trials to confirm the benefits of voxelotor in a broad range of patients with SCD,” she said.
The study was supported by Global Blood Therapeutics, the manufacturer of voxelotor. Dr. Bronté reported having no other conflicts of interest.
WASHINGTON – An investigational drug for sickle cell disease (SCD) boosted hemoglobin levels while reducing hospitalizations and transfusion needs by approximately two-thirds in a small cohort of severely affected patients.
Lanetta Bronté, MD, who presented the findings at the annual meeting of the Foundation for Sickle Cell Disease Research, reviewed the FDA’s requirements for allowing expanded access to an investigational drug. The key point, she said, is that expanded access may be granted “for treatment of patients with serious or immediately life-threatening diseases or conditions that lack therapeutic alternatives.” And, she said, the potential for benefit should outweigh potential risk of taking the investigational drug.
Current treatments don’t really address serious disease-related complications for patients with advanced SCD, she said. Furthermore, these patients will often be excluded from clinical trials of new SCD therapies.
Voxelotor is a novel small molecule that stabilizes the sickle hemoglobin molecule as a monomer in its high oxygen state. Thus, polymerization of the hemoglobin molecules is inhibited, which decreases the amount of red blood cell damage. Other beneficial effects of voxelotor include improved rheology and reduced hemolysis, as well as a boost to the oxygen-carrying capacity of the sickle hemoglobin molecules, Dr. Bronté explained.
For the seven patients in Dr. Bronté’s clinic who were granted expanded access to voxelator, the disease burden of their end-stage SCD was heavy. All participants had iron overload, five were receiving frequent transfusions, two required chronic oxygen supplementation, and four had severe fatigue. One patient had end-stage renal disease, and another had experienced multiple organ failure and prolonged hospitalizations.
None of the patients qualified for participation in ongoing clinical trials of voxelotor, said Dr. Bronté, who is president of the Foundation for Sickle Cell Disease Research. She also maintains a private practice in Hollywood, Fla.
The four women and three men, aged 22-67 years, were treated with voxelotor for a range of 6-17 months under the FDA’s Expanded Access Program. All patients saw rapid increases in serum hemoglobin, with increases of at least 1 g/dL in five of the seven. Across the participants, increases ranged from 0.5-5.4 g/dL at 24 weeks, up from baseline values of 5.2-7.8 g/dL.
One marker of clinical efficacy that Dr. Bronté and her coauthors examined was the number of hospitalizations for pain from vaso-occlusive crises (VOCs). In the 24 weeks before beginning voxelotor, participants had a summed total of 28 hospitalizations. In the first 24 weeks of treatment, there were a total of nine VOC-related hospitalizations among the participants, a 67% decrease.
The total number of red blood cell transfusions required by the study population declined by a similar proportion, from 33 during the 24 weeks before voxelotor treatment to 13 during the first 24 weeks of treatment, a decrease of 60%.
Individual patients saw improvements related to some of their most troublesome SCD complications, Dr. Bronté reported. All four patients whose oxygen saturation levels had been below 95% on room air saw oxygen saturations improve to 98%-99% on voxelotor. The two patients who had moderate or moderately severe depression, as assessed by the Patient Health Questionnaire 9-item, had minimal or no depression on retest after 24 weeks of voxelotor treatment.
Voxelotor was generally well tolerated at a 900-mg once-daily oral dose. One patient developed grade 2 diarrhea after increasing the dose to 1,500 mg, but symptoms resolved after returning to the 900-mg dose. Another patient had transient mild diarrhea on 900 mg of voxelotor; the symptoms resolved without changing or stopping the drug, Dr. Bronté said. There were no serious treatment-related adverse events.
Among this seriously ill population, two patients died after beginning voxelotor treatment, but both deaths were judged to be unrelated to the treatment. Dr. Bronté reported that the two deceased patients, one of whom was on voxelotor for 16 months and the other for 7 months, did experience reduced transfusion needs and reduced VOC-related hospitalizations while on the drug, experiences that were similar to the surviving members of the cohort.
“Voxelotor administered via compassionate use demonstrated large improvements in anemia and hemolysis, including in patients with lower baseline hemoglobin than studied in clinical trials to date,” Dr. Bronté said.
Taken together with clinical improvements and improved patient-focused outcomes among a severely affected population, “these data … support ongoing investigation in controlled clinical trials to confirm the benefits of voxelotor in a broad range of patients with SCD,” she said.
The study was supported by Global Blood Therapeutics, the manufacturer of voxelotor. Dr. Bronté reported having no other conflicts of interest.
REPORTING FROM FSCDR 2018
Key clinical point:
Major finding: Transfusion requirements were cut by 60% in the first 24 weeks on voxelotor.
Study details: Open label case series of seven patients with end-stage SCD at a single center.
Disclosures: The study was funded by Global Blood Therapeutics, which manufactures voxelotor. Dr. Bronté reported having no other conflicts of interest.
Sickle cell disease exacts a heavy vocational toll
WASHINGTON – Three-quarters of patients with sickle cell disease (SCD) reported missing work in the last year because of disease symptoms, according to results from a single-center study.
While the direct costs of SCD are easy to measure, it’s harder to capture the indirect costs patients may incur from this chronic, progressive disease, which range from lost days at work to the downstream consequences of “presenteeism.”
“Indirect costs are related to things that have value, but it’s a little bit harder to apply an exact value to it,” said Nicholas Vendetti of Pfizer. But this is a critical piece for understanding SCD, he said. “The burden of illness is unknown without productivity costs.”
Mr. Vendetti and his collaborators attempted to capture the indirect costs of SCD, and reported the results of a single-site study at the annual meeting of the Foundation for Sickle Cell Disease Research.
They recruited patients from Virginia Commonwealth University’s adult sickle cell clinic and trained interviewers to conduct structured interviews using the Institute for Medical Technology Assessment Productivity Cost Questionnaire. The interviewers asked about absenteeism, lost work, unpaid work activity, and “presenteeism,” defined as days when participants were at work but experienced decreased work output because of disease symptoms.
In the end, the study enrolled 186 patients aged 18 and older, a figure that “really exceeded what we expected when we started the protocol,” Mr. Vendetti said. Most participants were between the ages of 20 and 60 years – the most productive working years.
About 58% of participants were female. Nearly half (46%) had the HbSS genotype, while 30% had the HbSC genotype. About half (52%) were high school graduates, and about a third had some college. There were no advanced degrees earned in the study population, and 11.5% had not finished high school.
Initial questions about educational status and employment status “highlighted a very interesting aspect of the disease: 43.8% reported that they were currently unable to work as part of their disease process,” Mr. Vendetti said. Just 28% were employed for wages, 3% were self-employed, and about 7% reported being homemakers. The remainder were out of work, were students, or were retired.
Three-quarters of patients reported missing work in the last year because of SCD symptoms. This group reported missing a mean 36.75 days yearly. Assuming the average Virginia hourly wage of $25.53 per hour, this comes to an average of $7,506 in lost wages each year, Mr. Vendetti said.
Presenteeism had a large impact as well. Nearly 73% of patients said they were bothered at work – either psychologically or physically – by their symptoms in the last 4 weeks, and 90% over the past year. These patients estimated they were affected for about 100 working days yearly.
When asked on a scale of 0-10 how much work they were able to get done on days when their SCD was affecting productivity, “most patients are falling into that middle range” of a score of 4-6, Mr. Vendetti said. “Most patients are moderately affected.
“It’s hard to apply a dollar value to that, but it’s easy to see how it could affect the trajectory of your career,” he added.
Another aspect of the indirect cost of the sickle cell disease burden that’s even harder to tease out is whether those affected are unable to complete a significant amount of unpaid work. Again, about three-quarters of patients reported that SCD had affected their ability to do this kind of work, and these patients said this happened on an average 105 days each year.
Even though patients may not be hiring others to do housework they’re unable to complete, or to care for children on days when they’re too unwell to do so, that doesn’t mean there’s no impact on the patient and those around them, Mr. Vendetti said. “If you ask a family member or a friend for help, that creates a strain in the relationship.”
In terms of resources to address the indirect burden of SCD on careers, Mr. Vendetti pointed out that many states have vocational rehabilitation programs that offer a significant amount of support and assistance to help find a productive work path that still accommodates a chronic illness such as SCD. In Virginia, he said, individuals need to be on disability to avail themselves of the program.
Health care providers can educate themselves about these and other programs. “Most adult sickle cell disease patients didn’t even know they might be eligible” for vocational assistance, he said.
During discussion after the presentation, an audience member pointed out that parents and caregivers of children with SCD are probably also incurring significant indirect costs because of their care-giving burden and that this population should also be studied. Mr. Vendetti agreed. “This is potential that isn’t fulfilled” for all patients and families whose work and personal lives are so profoundly affected by SCD, he said. “This is a dream deferred.”
Mr. Vendetti is employed by Pfizer and is a Pfizer stockholder. A coauthor of the study is a Pfizer consultant.
WASHINGTON – Three-quarters of patients with sickle cell disease (SCD) reported missing work in the last year because of disease symptoms, according to results from a single-center study.
While the direct costs of SCD are easy to measure, it’s harder to capture the indirect costs patients may incur from this chronic, progressive disease, which range from lost days at work to the downstream consequences of “presenteeism.”
“Indirect costs are related to things that have value, but it’s a little bit harder to apply an exact value to it,” said Nicholas Vendetti of Pfizer. But this is a critical piece for understanding SCD, he said. “The burden of illness is unknown without productivity costs.”
Mr. Vendetti and his collaborators attempted to capture the indirect costs of SCD, and reported the results of a single-site study at the annual meeting of the Foundation for Sickle Cell Disease Research.
They recruited patients from Virginia Commonwealth University’s adult sickle cell clinic and trained interviewers to conduct structured interviews using the Institute for Medical Technology Assessment Productivity Cost Questionnaire. The interviewers asked about absenteeism, lost work, unpaid work activity, and “presenteeism,” defined as days when participants were at work but experienced decreased work output because of disease symptoms.
In the end, the study enrolled 186 patients aged 18 and older, a figure that “really exceeded what we expected when we started the protocol,” Mr. Vendetti said. Most participants were between the ages of 20 and 60 years – the most productive working years.
About 58% of participants were female. Nearly half (46%) had the HbSS genotype, while 30% had the HbSC genotype. About half (52%) were high school graduates, and about a third had some college. There were no advanced degrees earned in the study population, and 11.5% had not finished high school.
Initial questions about educational status and employment status “highlighted a very interesting aspect of the disease: 43.8% reported that they were currently unable to work as part of their disease process,” Mr. Vendetti said. Just 28% were employed for wages, 3% were self-employed, and about 7% reported being homemakers. The remainder were out of work, were students, or were retired.
Three-quarters of patients reported missing work in the last year because of SCD symptoms. This group reported missing a mean 36.75 days yearly. Assuming the average Virginia hourly wage of $25.53 per hour, this comes to an average of $7,506 in lost wages each year, Mr. Vendetti said.
Presenteeism had a large impact as well. Nearly 73% of patients said they were bothered at work – either psychologically or physically – by their symptoms in the last 4 weeks, and 90% over the past year. These patients estimated they were affected for about 100 working days yearly.
When asked on a scale of 0-10 how much work they were able to get done on days when their SCD was affecting productivity, “most patients are falling into that middle range” of a score of 4-6, Mr. Vendetti said. “Most patients are moderately affected.
“It’s hard to apply a dollar value to that, but it’s easy to see how it could affect the trajectory of your career,” he added.
Another aspect of the indirect cost of the sickle cell disease burden that’s even harder to tease out is whether those affected are unable to complete a significant amount of unpaid work. Again, about three-quarters of patients reported that SCD had affected their ability to do this kind of work, and these patients said this happened on an average 105 days each year.
Even though patients may not be hiring others to do housework they’re unable to complete, or to care for children on days when they’re too unwell to do so, that doesn’t mean there’s no impact on the patient and those around them, Mr. Vendetti said. “If you ask a family member or a friend for help, that creates a strain in the relationship.”
In terms of resources to address the indirect burden of SCD on careers, Mr. Vendetti pointed out that many states have vocational rehabilitation programs that offer a significant amount of support and assistance to help find a productive work path that still accommodates a chronic illness such as SCD. In Virginia, he said, individuals need to be on disability to avail themselves of the program.
Health care providers can educate themselves about these and other programs. “Most adult sickle cell disease patients didn’t even know they might be eligible” for vocational assistance, he said.
During discussion after the presentation, an audience member pointed out that parents and caregivers of children with SCD are probably also incurring significant indirect costs because of their care-giving burden and that this population should also be studied. Mr. Vendetti agreed. “This is potential that isn’t fulfilled” for all patients and families whose work and personal lives are so profoundly affected by SCD, he said. “This is a dream deferred.”
Mr. Vendetti is employed by Pfizer and is a Pfizer stockholder. A coauthor of the study is a Pfizer consultant.
WASHINGTON – Three-quarters of patients with sickle cell disease (SCD) reported missing work in the last year because of disease symptoms, according to results from a single-center study.
While the direct costs of SCD are easy to measure, it’s harder to capture the indirect costs patients may incur from this chronic, progressive disease, which range from lost days at work to the downstream consequences of “presenteeism.”
“Indirect costs are related to things that have value, but it’s a little bit harder to apply an exact value to it,” said Nicholas Vendetti of Pfizer. But this is a critical piece for understanding SCD, he said. “The burden of illness is unknown without productivity costs.”
Mr. Vendetti and his collaborators attempted to capture the indirect costs of SCD, and reported the results of a single-site study at the annual meeting of the Foundation for Sickle Cell Disease Research.
They recruited patients from Virginia Commonwealth University’s adult sickle cell clinic and trained interviewers to conduct structured interviews using the Institute for Medical Technology Assessment Productivity Cost Questionnaire. The interviewers asked about absenteeism, lost work, unpaid work activity, and “presenteeism,” defined as days when participants were at work but experienced decreased work output because of disease symptoms.
In the end, the study enrolled 186 patients aged 18 and older, a figure that “really exceeded what we expected when we started the protocol,” Mr. Vendetti said. Most participants were between the ages of 20 and 60 years – the most productive working years.
About 58% of participants were female. Nearly half (46%) had the HbSS genotype, while 30% had the HbSC genotype. About half (52%) were high school graduates, and about a third had some college. There were no advanced degrees earned in the study population, and 11.5% had not finished high school.
Initial questions about educational status and employment status “highlighted a very interesting aspect of the disease: 43.8% reported that they were currently unable to work as part of their disease process,” Mr. Vendetti said. Just 28% were employed for wages, 3% were self-employed, and about 7% reported being homemakers. The remainder were out of work, were students, or were retired.
Three-quarters of patients reported missing work in the last year because of SCD symptoms. This group reported missing a mean 36.75 days yearly. Assuming the average Virginia hourly wage of $25.53 per hour, this comes to an average of $7,506 in lost wages each year, Mr. Vendetti said.
Presenteeism had a large impact as well. Nearly 73% of patients said they were bothered at work – either psychologically or physically – by their symptoms in the last 4 weeks, and 90% over the past year. These patients estimated they were affected for about 100 working days yearly.
When asked on a scale of 0-10 how much work they were able to get done on days when their SCD was affecting productivity, “most patients are falling into that middle range” of a score of 4-6, Mr. Vendetti said. “Most patients are moderately affected.
“It’s hard to apply a dollar value to that, but it’s easy to see how it could affect the trajectory of your career,” he added.
Another aspect of the indirect cost of the sickle cell disease burden that’s even harder to tease out is whether those affected are unable to complete a significant amount of unpaid work. Again, about three-quarters of patients reported that SCD had affected their ability to do this kind of work, and these patients said this happened on an average 105 days each year.
Even though patients may not be hiring others to do housework they’re unable to complete, or to care for children on days when they’re too unwell to do so, that doesn’t mean there’s no impact on the patient and those around them, Mr. Vendetti said. “If you ask a family member or a friend for help, that creates a strain in the relationship.”
In terms of resources to address the indirect burden of SCD on careers, Mr. Vendetti pointed out that many states have vocational rehabilitation programs that offer a significant amount of support and assistance to help find a productive work path that still accommodates a chronic illness such as SCD. In Virginia, he said, individuals need to be on disability to avail themselves of the program.
Health care providers can educate themselves about these and other programs. “Most adult sickle cell disease patients didn’t even know they might be eligible” for vocational assistance, he said.
During discussion after the presentation, an audience member pointed out that parents and caregivers of children with SCD are probably also incurring significant indirect costs because of their care-giving burden and that this population should also be studied. Mr. Vendetti agreed. “This is potential that isn’t fulfilled” for all patients and families whose work and personal lives are so profoundly affected by SCD, he said. “This is a dream deferred.”
Mr. Vendetti is employed by Pfizer and is a Pfizer stockholder. A coauthor of the study is a Pfizer consultant.
REPORTING FROM FSCDR 2018
Key clinical point:
Major finding: Three-quarters of patients reported missing work in the last year because of SCD symptoms. This group reported missing a mean 37 days yearly.
Study details: Single-site survey-based study of 186 adults with SCD.
Disclosures: Pfizer sponsored the study. Mr. Vendetti is employed by Pfizer and holds Pfizer stock. A study coauthor is a Pfizer consultant.
Family engagement can buffer early cognitive hit from SCD
WASHINGTON – Can early family interventions help children with sickle cell disease (SCD) stay on track for normal cognitive development?
Given the stakes – even young children with SCD have a high risk of ischemic cerebral insults, with significant downstream cognitive deficits – these interventions are sorely needed, said Allison King, MD, PhD, of Washington University, St. Louis.
Speaking at the annual meeting of the Foundation for Sickle Cell Disease Research, Dr. King shared her institution’s suite of interventions, which are aimed at giving infants and toddlers early home enrichment through parent education and engagement.
Dr. King reviewed some of the factors that are known to be associated with intelligence quotient (IQ) changes in individuals with SCD. The single largest impact comes with an overt stroke, which drops IQ by an average 10 points. A “silent” subclinical stroke is associated with a mean 5-point decrease, while hypoxemia is associated with diminution in IQ of about 0.75 points.
On the other hand, having a parent with at least some college education is associated with a robust 6-point boost in IQ, Dr. King said.
Even if the disease results in a mean 5-point drop in IQ for the national population of children with SCD, this would result in the bell curve of intellectual ability for this cohort shifting significantly to the left, Dr. King said. Instead of 6 million children with SCD falling into the “intellectually disabled” category of those with IQs less than 70, the number would climb to 9.4 million, a 57% increase.
Cognitive impairment can be evident by the toddler years. Across the literature, 46%-58% of young children with SCD have been found to have risk for developmental delay or to show frank delay by 12-36 months of age, Dr. King said. Factors associated with risk of delay include low hemoglobin level, disease phenotype, positive transcranial Doppler findings, and – importantly – parental education, income, and perceived helplessness.
Dr. King and her collaborators have tackled the home environment to address some of these potentially remediable social factors. They hypothesized that a parent education program that boosts the quality of parent-child interactions would help children with SCD have better developmental outcomes.
She and her colleagues designed a prospective single-arm pilot study that enrolled children with SCD from birth to 36 months of age, along with a parent or caregiver (Pediatr Blood Cancer. 2016 Dec;63[12]:2131-8).
Over a period of continuous enrollment of up to 2 years, the families received a monthly visit from a home educator. During these visits, the educators delivered a validated “Born to Learn” curriculum that uses a parents-as-teachers model.
Of the 35 children, 15 (43%) were female. At enrollment, the children were a mean 5 months of age and their primary caregiver was a mean 25 years old. The children’s mean age of exit from the study was 26 months. Most patients had either the HbSS (46%) or the HbSC (43%) phenotype. At enrollment, the mean peripheral oxygen saturation was 100%, and hematocrit was a mean 27.9%.
“The parenting intervention improved cognition and language,” Dr. King said, especially in the domains of cognitive performance and expressive language, which both saw significant age-normed score improvements over the course of the study (P = .016 and .002, respectively).
Among the pre- and poststudy measures that were used was the Home Observation for Measurement of Environment tool, said Dr. King. This observer-completed scale measures parent/caregiver responsivity, acceptance, and organization. Also, the parent’s level of organization and involvement is assessed, as are available learning materials and variety of resources and enrichment.
Scores improved here, too, particularly in the domains of organization and the amount of learning materials available at home (P less than .05 for both). There was a numeric improvement in the overall score, but the figure wasn’t statistically significant.
Dr. King used recent research to bring home the importance of early intervention to support cognitive development in children with SCD. A recent meta-analysis found that 50.3% of SCD patients will have had a silent brain infarct by 30 years of age (Blood. 2016 Apr 21;127[16]:2038-40). The same publication, she said, cited work that found a prevalence of silent infarcts ranging from more than 25% by the age of 5 years to 19%-28% at 8 years.
But “parent education impacts IQ more than silent infarcts,” she said. In her work, the highest predicted IQs are seen in young patients with no infarcts and whose parents have had some college education. Perhaps surprisingly, she said, the next highest IQ tier consists of patients who have detectable infarcts, but whose parents have had at least some college education. These patients’ predicted IQs were higher than those who had no infarcts but whose parents had no more than a high school education, as well as children with the double hit of an infarct and parents with no college education.
Putting these puzzle pieces together matters for long-term outcomes, Dr. King said. Socioeconomic status is the strongest predictor of grade retention for children with SCD, with the poorest quartile in a study of 536 pediatric SCD patients having an odds ratio of 6.4 for grade retention, compared with the highest quartile (P = .001). Notably, children in the lowest quartile lived in homes where the per capita income was less than $3,000 (Am J Hematol. 2014;89[10]:e188-92). This highlights the “abject poverty” many of these families face, Dr. King said.
Children in this poorest quartile, especially boys, fared poorly going forward. “By age 15, 65% of poor males with sickle cell anemia fail a grade,” Dr. King said. The frequent absenteeism occasioned by hospital stays, clinic visits, and days at home with pain mount to an average of 15-22 missed school days annually, she said, adding that “absenteeism is an important predictor of dropout.”
These trends are brought forward into the workplace, with adults who have SCD being less likely to be employed if their IQs are lower. The association is particularly strong for processing speed, according to one study (J Clin Exp Neuropsychol. 2016 Aug;38[6]:661-71).
Dr. King outlined some concrete steps that those caring for children with SCD can take to maximize their chances for school success, acknowledging that time and resource constraints will vary by practice setting. These include completing an in-clinic educational inventory, asking about recent school performance, and if indicated, referring for neuropsychology evaluation to be shared with the school.
Physicians also can work to engage institutional resources for advocacy and communication with the school.
Parents can be encouraged to request a 504 plan, a federally mandated set of accommodations. For children with SCD, these might include setting up tutoring for periods when the child is homebound, allowing a water bottle and frequent bathroom breaks since hydration is critical for children with SCD, and allowing extra time for testing if processing speed is an issue.
An additional education step is the individualized education plan, or IEP, which can include instruction in smaller groups or teaching that’s modified for special learning needs; alternative methods of assessments; and, for older children, consideration of a vocational education path to complete high school.
Dr. King reported having no conflicts of interest.
WASHINGTON – Can early family interventions help children with sickle cell disease (SCD) stay on track for normal cognitive development?
Given the stakes – even young children with SCD have a high risk of ischemic cerebral insults, with significant downstream cognitive deficits – these interventions are sorely needed, said Allison King, MD, PhD, of Washington University, St. Louis.
Speaking at the annual meeting of the Foundation for Sickle Cell Disease Research, Dr. King shared her institution’s suite of interventions, which are aimed at giving infants and toddlers early home enrichment through parent education and engagement.
Dr. King reviewed some of the factors that are known to be associated with intelligence quotient (IQ) changes in individuals with SCD. The single largest impact comes with an overt stroke, which drops IQ by an average 10 points. A “silent” subclinical stroke is associated with a mean 5-point decrease, while hypoxemia is associated with diminution in IQ of about 0.75 points.
On the other hand, having a parent with at least some college education is associated with a robust 6-point boost in IQ, Dr. King said.
Even if the disease results in a mean 5-point drop in IQ for the national population of children with SCD, this would result in the bell curve of intellectual ability for this cohort shifting significantly to the left, Dr. King said. Instead of 6 million children with SCD falling into the “intellectually disabled” category of those with IQs less than 70, the number would climb to 9.4 million, a 57% increase.
Cognitive impairment can be evident by the toddler years. Across the literature, 46%-58% of young children with SCD have been found to have risk for developmental delay or to show frank delay by 12-36 months of age, Dr. King said. Factors associated with risk of delay include low hemoglobin level, disease phenotype, positive transcranial Doppler findings, and – importantly – parental education, income, and perceived helplessness.
Dr. King and her collaborators have tackled the home environment to address some of these potentially remediable social factors. They hypothesized that a parent education program that boosts the quality of parent-child interactions would help children with SCD have better developmental outcomes.
She and her colleagues designed a prospective single-arm pilot study that enrolled children with SCD from birth to 36 months of age, along with a parent or caregiver (Pediatr Blood Cancer. 2016 Dec;63[12]:2131-8).
Over a period of continuous enrollment of up to 2 years, the families received a monthly visit from a home educator. During these visits, the educators delivered a validated “Born to Learn” curriculum that uses a parents-as-teachers model.
Of the 35 children, 15 (43%) were female. At enrollment, the children were a mean 5 months of age and their primary caregiver was a mean 25 years old. The children’s mean age of exit from the study was 26 months. Most patients had either the HbSS (46%) or the HbSC (43%) phenotype. At enrollment, the mean peripheral oxygen saturation was 100%, and hematocrit was a mean 27.9%.
“The parenting intervention improved cognition and language,” Dr. King said, especially in the domains of cognitive performance and expressive language, which both saw significant age-normed score improvements over the course of the study (P = .016 and .002, respectively).
Among the pre- and poststudy measures that were used was the Home Observation for Measurement of Environment tool, said Dr. King. This observer-completed scale measures parent/caregiver responsivity, acceptance, and organization. Also, the parent’s level of organization and involvement is assessed, as are available learning materials and variety of resources and enrichment.
Scores improved here, too, particularly in the domains of organization and the amount of learning materials available at home (P less than .05 for both). There was a numeric improvement in the overall score, but the figure wasn’t statistically significant.
Dr. King used recent research to bring home the importance of early intervention to support cognitive development in children with SCD. A recent meta-analysis found that 50.3% of SCD patients will have had a silent brain infarct by 30 years of age (Blood. 2016 Apr 21;127[16]:2038-40). The same publication, she said, cited work that found a prevalence of silent infarcts ranging from more than 25% by the age of 5 years to 19%-28% at 8 years.
But “parent education impacts IQ more than silent infarcts,” she said. In her work, the highest predicted IQs are seen in young patients with no infarcts and whose parents have had some college education. Perhaps surprisingly, she said, the next highest IQ tier consists of patients who have detectable infarcts, but whose parents have had at least some college education. These patients’ predicted IQs were higher than those who had no infarcts but whose parents had no more than a high school education, as well as children with the double hit of an infarct and parents with no college education.
Putting these puzzle pieces together matters for long-term outcomes, Dr. King said. Socioeconomic status is the strongest predictor of grade retention for children with SCD, with the poorest quartile in a study of 536 pediatric SCD patients having an odds ratio of 6.4 for grade retention, compared with the highest quartile (P = .001). Notably, children in the lowest quartile lived in homes where the per capita income was less than $3,000 (Am J Hematol. 2014;89[10]:e188-92). This highlights the “abject poverty” many of these families face, Dr. King said.
Children in this poorest quartile, especially boys, fared poorly going forward. “By age 15, 65% of poor males with sickle cell anemia fail a grade,” Dr. King said. The frequent absenteeism occasioned by hospital stays, clinic visits, and days at home with pain mount to an average of 15-22 missed school days annually, she said, adding that “absenteeism is an important predictor of dropout.”
These trends are brought forward into the workplace, with adults who have SCD being less likely to be employed if their IQs are lower. The association is particularly strong for processing speed, according to one study (J Clin Exp Neuropsychol. 2016 Aug;38[6]:661-71).
Dr. King outlined some concrete steps that those caring for children with SCD can take to maximize their chances for school success, acknowledging that time and resource constraints will vary by practice setting. These include completing an in-clinic educational inventory, asking about recent school performance, and if indicated, referring for neuropsychology evaluation to be shared with the school.
Physicians also can work to engage institutional resources for advocacy and communication with the school.
Parents can be encouraged to request a 504 plan, a federally mandated set of accommodations. For children with SCD, these might include setting up tutoring for periods when the child is homebound, allowing a water bottle and frequent bathroom breaks since hydration is critical for children with SCD, and allowing extra time for testing if processing speed is an issue.
An additional education step is the individualized education plan, or IEP, which can include instruction in smaller groups or teaching that’s modified for special learning needs; alternative methods of assessments; and, for older children, consideration of a vocational education path to complete high school.
Dr. King reported having no conflicts of interest.
WASHINGTON – Can early family interventions help children with sickle cell disease (SCD) stay on track for normal cognitive development?
Given the stakes – even young children with SCD have a high risk of ischemic cerebral insults, with significant downstream cognitive deficits – these interventions are sorely needed, said Allison King, MD, PhD, of Washington University, St. Louis.
Speaking at the annual meeting of the Foundation for Sickle Cell Disease Research, Dr. King shared her institution’s suite of interventions, which are aimed at giving infants and toddlers early home enrichment through parent education and engagement.
Dr. King reviewed some of the factors that are known to be associated with intelligence quotient (IQ) changes in individuals with SCD. The single largest impact comes with an overt stroke, which drops IQ by an average 10 points. A “silent” subclinical stroke is associated with a mean 5-point decrease, while hypoxemia is associated with diminution in IQ of about 0.75 points.
On the other hand, having a parent with at least some college education is associated with a robust 6-point boost in IQ, Dr. King said.
Even if the disease results in a mean 5-point drop in IQ for the national population of children with SCD, this would result in the bell curve of intellectual ability for this cohort shifting significantly to the left, Dr. King said. Instead of 6 million children with SCD falling into the “intellectually disabled” category of those with IQs less than 70, the number would climb to 9.4 million, a 57% increase.
Cognitive impairment can be evident by the toddler years. Across the literature, 46%-58% of young children with SCD have been found to have risk for developmental delay or to show frank delay by 12-36 months of age, Dr. King said. Factors associated with risk of delay include low hemoglobin level, disease phenotype, positive transcranial Doppler findings, and – importantly – parental education, income, and perceived helplessness.
Dr. King and her collaborators have tackled the home environment to address some of these potentially remediable social factors. They hypothesized that a parent education program that boosts the quality of parent-child interactions would help children with SCD have better developmental outcomes.
She and her colleagues designed a prospective single-arm pilot study that enrolled children with SCD from birth to 36 months of age, along with a parent or caregiver (Pediatr Blood Cancer. 2016 Dec;63[12]:2131-8).
Over a period of continuous enrollment of up to 2 years, the families received a monthly visit from a home educator. During these visits, the educators delivered a validated “Born to Learn” curriculum that uses a parents-as-teachers model.
Of the 35 children, 15 (43%) were female. At enrollment, the children were a mean 5 months of age and their primary caregiver was a mean 25 years old. The children’s mean age of exit from the study was 26 months. Most patients had either the HbSS (46%) or the HbSC (43%) phenotype. At enrollment, the mean peripheral oxygen saturation was 100%, and hematocrit was a mean 27.9%.
“The parenting intervention improved cognition and language,” Dr. King said, especially in the domains of cognitive performance and expressive language, which both saw significant age-normed score improvements over the course of the study (P = .016 and .002, respectively).
Among the pre- and poststudy measures that were used was the Home Observation for Measurement of Environment tool, said Dr. King. This observer-completed scale measures parent/caregiver responsivity, acceptance, and organization. Also, the parent’s level of organization and involvement is assessed, as are available learning materials and variety of resources and enrichment.
Scores improved here, too, particularly in the domains of organization and the amount of learning materials available at home (P less than .05 for both). There was a numeric improvement in the overall score, but the figure wasn’t statistically significant.
Dr. King used recent research to bring home the importance of early intervention to support cognitive development in children with SCD. A recent meta-analysis found that 50.3% of SCD patients will have had a silent brain infarct by 30 years of age (Blood. 2016 Apr 21;127[16]:2038-40). The same publication, she said, cited work that found a prevalence of silent infarcts ranging from more than 25% by the age of 5 years to 19%-28% at 8 years.
But “parent education impacts IQ more than silent infarcts,” she said. In her work, the highest predicted IQs are seen in young patients with no infarcts and whose parents have had some college education. Perhaps surprisingly, she said, the next highest IQ tier consists of patients who have detectable infarcts, but whose parents have had at least some college education. These patients’ predicted IQs were higher than those who had no infarcts but whose parents had no more than a high school education, as well as children with the double hit of an infarct and parents with no college education.
Putting these puzzle pieces together matters for long-term outcomes, Dr. King said. Socioeconomic status is the strongest predictor of grade retention for children with SCD, with the poorest quartile in a study of 536 pediatric SCD patients having an odds ratio of 6.4 for grade retention, compared with the highest quartile (P = .001). Notably, children in the lowest quartile lived in homes where the per capita income was less than $3,000 (Am J Hematol. 2014;89[10]:e188-92). This highlights the “abject poverty” many of these families face, Dr. King said.
Children in this poorest quartile, especially boys, fared poorly going forward. “By age 15, 65% of poor males with sickle cell anemia fail a grade,” Dr. King said. The frequent absenteeism occasioned by hospital stays, clinic visits, and days at home with pain mount to an average of 15-22 missed school days annually, she said, adding that “absenteeism is an important predictor of dropout.”
These trends are brought forward into the workplace, with adults who have SCD being less likely to be employed if their IQs are lower. The association is particularly strong for processing speed, according to one study (J Clin Exp Neuropsychol. 2016 Aug;38[6]:661-71).
Dr. King outlined some concrete steps that those caring for children with SCD can take to maximize their chances for school success, acknowledging that time and resource constraints will vary by practice setting. These include completing an in-clinic educational inventory, asking about recent school performance, and if indicated, referring for neuropsychology evaluation to be shared with the school.
Physicians also can work to engage institutional resources for advocacy and communication with the school.
Parents can be encouraged to request a 504 plan, a federally mandated set of accommodations. For children with SCD, these might include setting up tutoring for periods when the child is homebound, allowing a water bottle and frequent bathroom breaks since hydration is critical for children with SCD, and allowing extra time for testing if processing speed is an issue.
An additional education step is the individualized education plan, or IEP, which can include instruction in smaller groups or teaching that’s modified for special learning needs; alternative methods of assessments; and, for older children, consideration of a vocational education path to complete high school.
Dr. King reported having no conflicts of interest.
EXPERT ANALYSIS FROM FSCDR 2018