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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.
CHMP backs proposed biosimilars of pegfilgrastim
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.
If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).
Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.
According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.
The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.
The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.
Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.
If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).
Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.
According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.
The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.
The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.
Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.
If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).
Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.
According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.
The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.
The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.
Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.
Sequencing informs prognosis after HSCT in MDS
Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.
Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.
“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.
“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”
Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.
The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.
The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.
The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.
Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.
Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).
Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).
The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).
The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.
In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).
“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.
He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.
The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”
With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).
This study was supported by grants from the Leukemia and Lymphoma Society and other groups.
Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.
Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.
“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.
“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”
Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.
The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.
The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.
The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.
Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.
Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).
Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).
The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).
The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.
In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).
“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.
He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.
The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”
With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).
This study was supported by grants from the Leukemia and Lymphoma Society and other groups.
Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.
Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.
“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.
“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”
Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.
The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.
The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.
The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.
Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.
Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).
Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).
The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).
The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.
In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).
“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.
He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.
The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”
With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).
This study was supported by grants from the Leukemia and Lymphoma Society and other groups.
HIF1A could be therapeutic target for MDS
The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.
Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.
Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.
Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.
The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.
The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.
The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.
“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.
“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”
Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.
The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.
The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.
Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.
This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.
The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.
Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.
Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.
Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.
The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.
The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.
The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.
“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.
“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”
Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.
The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.
The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.
Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.
This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.
The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.
Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.
Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.
Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.
The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.
The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.
The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.
“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.
“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”
Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.
The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.
The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.
Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.
This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.
Research may help explain how VOCs occur
Researchers say they have gained new insight that may help explain how vaso-occlusive crises (VOCs) occur in patients with sickle cell disease (SCD).
The team assessed how red blood cell (RBC) adhesion and polymerization of deoxygenated sickle hemoglobin affect the mechanisms underlying VOCs.
Experiments showed that hypoxia enhances sickle RBC adherence, and hemoglobin S polymerization enhances adherence for sickle reticulocytes and mature erythrocytes.
However, sickle reticulocytes have “unique adhesion dynamics” and therefore appear more likely to cause VOCs.
The researchers described these discoveries in an article set to be published this week in the Proceedings of the National Academy of Sciences.
To investigate how RBCs interact with blood vessels to set off a VOC, the researchers built a microfluidic system that mimics post-capillary vessels. These vessels, which carry deoxygenated blood away from the capillaries, are where vaso-occlusions are most likely to occur.
The microfluidic system is designed to allow the researchers to control the oxygen level. The team used the system to test blood from eight SCD patients.
The researchers found that, under hypoxic conditions, sickle RBCs are two to four times more likely to adhere to the blood vessel walls than they are when oxygen levels are normal.
The team also found that hemoglobin S polymerization enhances the adherence of sickle reticulocytes and sickle mature erythrocytes. The hemoglobin S forms stiff fibers that grow and push the cell membrane outward, and these fibers help the cells adhere more firmly to the lining of the blood vessel.
“There has been little understanding of why, under hypoxia, there is much more adhesion,” said study author Subra Suresh, DSc, of Nanyang Technological University in Singapore.
“The experiments of this study provide some key insights into the processes and mechanisms responsible for increased adhesion.”
The researchers also found that, in SCD patients, reticulocytes are more likely than mature erythrocytes to adhere to blood vessels.
“We observed the growth of sickle hemoglobin fibers stretching reticulocytes within minutes,” said study author Dimitrios Papageorgiou, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It looks like they’re trying to grab more of the surface and adhere more strongly.”
The researchers said these and other findings suggest polymerization and adhesion stimulate each other.
The team now hopes to devise a more complete model of vaso-occlusion that combines their new findings with previous work. The previous work involved measuring how long it takes SCD patients’ blood cells to stiffen, making them more likely to block blood flow in tiny blood vessels.
The researchers also hope their findings might help them devise a way to predict VOCs in individual SCD patients.
Researchers say they have gained new insight that may help explain how vaso-occlusive crises (VOCs) occur in patients with sickle cell disease (SCD).
The team assessed how red blood cell (RBC) adhesion and polymerization of deoxygenated sickle hemoglobin affect the mechanisms underlying VOCs.
Experiments showed that hypoxia enhances sickle RBC adherence, and hemoglobin S polymerization enhances adherence for sickle reticulocytes and mature erythrocytes.
However, sickle reticulocytes have “unique adhesion dynamics” and therefore appear more likely to cause VOCs.
The researchers described these discoveries in an article set to be published this week in the Proceedings of the National Academy of Sciences.
To investigate how RBCs interact with blood vessels to set off a VOC, the researchers built a microfluidic system that mimics post-capillary vessels. These vessels, which carry deoxygenated blood away from the capillaries, are where vaso-occlusions are most likely to occur.
The microfluidic system is designed to allow the researchers to control the oxygen level. The team used the system to test blood from eight SCD patients.
The researchers found that, under hypoxic conditions, sickle RBCs are two to four times more likely to adhere to the blood vessel walls than they are when oxygen levels are normal.
The team also found that hemoglobin S polymerization enhances the adherence of sickle reticulocytes and sickle mature erythrocytes. The hemoglobin S forms stiff fibers that grow and push the cell membrane outward, and these fibers help the cells adhere more firmly to the lining of the blood vessel.
“There has been little understanding of why, under hypoxia, there is much more adhesion,” said study author Subra Suresh, DSc, of Nanyang Technological University in Singapore.
“The experiments of this study provide some key insights into the processes and mechanisms responsible for increased adhesion.”
The researchers also found that, in SCD patients, reticulocytes are more likely than mature erythrocytes to adhere to blood vessels.
“We observed the growth of sickle hemoglobin fibers stretching reticulocytes within minutes,” said study author Dimitrios Papageorgiou, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It looks like they’re trying to grab more of the surface and adhere more strongly.”
The researchers said these and other findings suggest polymerization and adhesion stimulate each other.
The team now hopes to devise a more complete model of vaso-occlusion that combines their new findings with previous work. The previous work involved measuring how long it takes SCD patients’ blood cells to stiffen, making them more likely to block blood flow in tiny blood vessels.
The researchers also hope their findings might help them devise a way to predict VOCs in individual SCD patients.
Researchers say they have gained new insight that may help explain how vaso-occlusive crises (VOCs) occur in patients with sickle cell disease (SCD).
The team assessed how red blood cell (RBC) adhesion and polymerization of deoxygenated sickle hemoglobin affect the mechanisms underlying VOCs.
Experiments showed that hypoxia enhances sickle RBC adherence, and hemoglobin S polymerization enhances adherence for sickle reticulocytes and mature erythrocytes.
However, sickle reticulocytes have “unique adhesion dynamics” and therefore appear more likely to cause VOCs.
The researchers described these discoveries in an article set to be published this week in the Proceedings of the National Academy of Sciences.
To investigate how RBCs interact with blood vessels to set off a VOC, the researchers built a microfluidic system that mimics post-capillary vessels. These vessels, which carry deoxygenated blood away from the capillaries, are where vaso-occlusions are most likely to occur.
The microfluidic system is designed to allow the researchers to control the oxygen level. The team used the system to test blood from eight SCD patients.
The researchers found that, under hypoxic conditions, sickle RBCs are two to four times more likely to adhere to the blood vessel walls than they are when oxygen levels are normal.
The team also found that hemoglobin S polymerization enhances the adherence of sickle reticulocytes and sickle mature erythrocytes. The hemoglobin S forms stiff fibers that grow and push the cell membrane outward, and these fibers help the cells adhere more firmly to the lining of the blood vessel.
“There has been little understanding of why, under hypoxia, there is much more adhesion,” said study author Subra Suresh, DSc, of Nanyang Technological University in Singapore.
“The experiments of this study provide some key insights into the processes and mechanisms responsible for increased adhesion.”
The researchers also found that, in SCD patients, reticulocytes are more likely than mature erythrocytes to adhere to blood vessels.
“We observed the growth of sickle hemoglobin fibers stretching reticulocytes within minutes,” said study author Dimitrios Papageorgiou, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It looks like they’re trying to grab more of the surface and adhere more strongly.”
The researchers said these and other findings suggest polymerization and adhesion stimulate each other.
The team now hopes to devise a more complete model of vaso-occlusion that combines their new findings with previous work. The previous work involved measuring how long it takes SCD patients’ blood cells to stiffen, making them more likely to block blood flow in tiny blood vessels.
The researchers also hope their findings might help them devise a way to predict VOCs in individual SCD patients.
AMP publishes report on DNA variants in CMNs
A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).
The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.
The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.
The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.
“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.
“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”
The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.
However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.
AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.
The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.
“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.
A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).
The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.
The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.
The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.
“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.
“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”
The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.
However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.
AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.
The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.
“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.
A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).
The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.
The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.
The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.
“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.
“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”
The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.
However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.
AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.
The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.
“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.
Blood disorders researcher is finalist for Trailblazer Prize
Daniel Bauer, MD, PhD, a pediatric hematologist and blood disorders researcher in Boston, is one of three finalists for the inaugural Trailblazer Prize for Clinician-Scientists, which is awarded by the Foundation for the National Institutes of Health.
Dr. Bauer, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, was selected based on his research using genome editing to tease out the causes of blood disorders, such as sickle cell disease and beta-thalassemia.
All three finalists for the Trailblazer Prize are early career clinician-scientists whose work has the potential to or has led to innovations in patient care, according to the Foundation for the National Institutes of Health.
The other two finalists are Jaehyuk Choi, MD, PhD, of Northwestern University in Chicago and Michael Fox, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.
Dr. Choi was selected for using genomics to identify mutations in skin cells that can lead to autoinflammatory diseases and cancer. Dr. Fox was selected for the development of innovative techniques to map human brain connectivity that can be used in novel treatments for Parkinson’s disease and depression.
The winner will be announced during a ceremony in Washington on Oct. 24, 2018, and will receive a $10,000 honorarium.
Daniel Bauer, MD, PhD, a pediatric hematologist and blood disorders researcher in Boston, is one of three finalists for the inaugural Trailblazer Prize for Clinician-Scientists, which is awarded by the Foundation for the National Institutes of Health.
Dr. Bauer, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, was selected based on his research using genome editing to tease out the causes of blood disorders, such as sickle cell disease and beta-thalassemia.
All three finalists for the Trailblazer Prize are early career clinician-scientists whose work has the potential to or has led to innovations in patient care, according to the Foundation for the National Institutes of Health.
The other two finalists are Jaehyuk Choi, MD, PhD, of Northwestern University in Chicago and Michael Fox, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.
Dr. Choi was selected for using genomics to identify mutations in skin cells that can lead to autoinflammatory diseases and cancer. Dr. Fox was selected for the development of innovative techniques to map human brain connectivity that can be used in novel treatments for Parkinson’s disease and depression.
The winner will be announced during a ceremony in Washington on Oct. 24, 2018, and will receive a $10,000 honorarium.
Daniel Bauer, MD, PhD, a pediatric hematologist and blood disorders researcher in Boston, is one of three finalists for the inaugural Trailblazer Prize for Clinician-Scientists, which is awarded by the Foundation for the National Institutes of Health.
Dr. Bauer, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, was selected based on his research using genome editing to tease out the causes of blood disorders, such as sickle cell disease and beta-thalassemia.
All three finalists for the Trailblazer Prize are early career clinician-scientists whose work has the potential to or has led to innovations in patient care, according to the Foundation for the National Institutes of Health.
The other two finalists are Jaehyuk Choi, MD, PhD, of Northwestern University in Chicago and Michael Fox, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.
Dr. Choi was selected for using genomics to identify mutations in skin cells that can lead to autoinflammatory diseases and cancer. Dr. Fox was selected for the development of innovative techniques to map human brain connectivity that can be used in novel treatments for Parkinson’s disease and depression.
The winner will be announced during a ceremony in Washington on Oct. 24, 2018, and will receive a $10,000 honorarium.
FDA grants priority review to drug for PNH
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.
With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.
The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.
PNH-301 trial
This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).
Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.
Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.
The study’s co-primary endpoints are:
- Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
- Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.
ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.
ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:
- Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
- Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
- Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
- Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).
Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.
One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.
Switch study
This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.
ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.
Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.
Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:
- The proportion of patients with breakthrough hemolysis
- The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
- The proportion of patients avoiding transfusion
- The proportion of patients with stabilized hemoglobin levels.
ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.
There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.
With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.
The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.
PNH-301 trial
This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).
Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.
Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.
The study’s co-primary endpoints are:
- Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
- Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.
ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.
ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:
- Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
- Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
- Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
- Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).
Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.
One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.
Switch study
This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.
ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.
Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.
Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:
- The proportion of patients with breakthrough hemolysis
- The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
- The proportion of patients avoiding transfusion
- The proportion of patients with stabilized hemoglobin levels.
ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.
There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.
With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.
The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.
PNH-301 trial
This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).
Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.
Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.
The study’s co-primary endpoints are:
- Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
- Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.
ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.
ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:
- Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
- Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
- Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
- Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).
Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.
One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.
Switch study
This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.
ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.
Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.
Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:
- The proportion of patients with breakthrough hemolysis
- The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
- The proportion of patients avoiding transfusion
- The proportion of patients with stabilized hemoglobin levels.
ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.
There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.
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.
Partial hold placed on trial of drug for AML, MDS
The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.
In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The partial clinical hold applies to the 12.2 mg/m2 dose of OXi4503.
The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m2.
The agency said additional data on patients receiving OXi4503 at 9.76 mg/m2 must be evaluated before dosing at 12.2 mg/m2 can be resumed.
The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m2 dose level.
One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.
Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.
The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.
“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.
About OXi4503
According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.
This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.
OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.
In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.
Clinical trials
In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.
The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.
The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.
Results from this study were presented at the 2013 ASH Annual Meeting.
In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.
The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.
The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.
The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.
The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.
In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The partial clinical hold applies to the 12.2 mg/m2 dose of OXi4503.
The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m2.
The agency said additional data on patients receiving OXi4503 at 9.76 mg/m2 must be evaluated before dosing at 12.2 mg/m2 can be resumed.
The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m2 dose level.
One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.
Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.
The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.
“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.
About OXi4503
According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.
This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.
OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.
In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.
Clinical trials
In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.
The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.
The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.
Results from this study were presented at the 2013 ASH Annual Meeting.
In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.
The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.
The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.
The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.
The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.
In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The partial clinical hold applies to the 12.2 mg/m2 dose of OXi4503.
The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m2.
The agency said additional data on patients receiving OXi4503 at 9.76 mg/m2 must be evaluated before dosing at 12.2 mg/m2 can be resumed.
The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m2 dose level.
One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.
Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.
The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.
“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.
About OXi4503
According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.
This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.
OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.
In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.
Clinical trials
In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.
The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.
The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.
Results from this study were presented at the 2013 ASH Annual Meeting.
In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.
The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.
The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.
The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.