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ASH: Genes tag increased risk for avascular necrosis in ALL patients under age 10
ORLANDO – Variants in mesenchymal stem cell genes that are important to bone and fat differentiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukemia, Dr. Seth E. Karol, of St. Jude Children’s Research Hospital in Memphis, reported at the annual meeting of the American Society of Hematology.
In a second study of children with ALL, Dr. Peter D. Cole, of Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture.
The pathophysiology of bony morbidity differs depending on the patient’s age, Dr. Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.”
Bony morbidity is more common in children over age 10 with ALL, and related to exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10-20 years old.
However, children under 10 make up 75% of new pediatric ALL diagnoses, Dr. Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases.
In Dr. Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.
The research targeted common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate.
Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures.
Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thymidylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes.
Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; P=0.019).
Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or RBC folate at any time point during therapy.
In the study reported by Dr. Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol.
Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Genes associated with the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways.
Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data.
Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways.
“Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3-6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr. Karol reported.
Dr. Cole and Dr. Karol had no relevant financial disclosures.
On Twitter @maryjodales
ORLANDO – Variants in mesenchymal stem cell genes that are important to bone and fat differentiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukemia, Dr. Seth E. Karol, of St. Jude Children’s Research Hospital in Memphis, reported at the annual meeting of the American Society of Hematology.
In a second study of children with ALL, Dr. Peter D. Cole, of Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture.
The pathophysiology of bony morbidity differs depending on the patient’s age, Dr. Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.”
Bony morbidity is more common in children over age 10 with ALL, and related to exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10-20 years old.
However, children under 10 make up 75% of new pediatric ALL diagnoses, Dr. Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases.
In Dr. Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.
The research targeted common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate.
Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures.
Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thymidylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes.
Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; P=0.019).
Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or RBC folate at any time point during therapy.
In the study reported by Dr. Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol.
Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Genes associated with the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways.
Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data.
Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways.
“Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3-6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr. Karol reported.
Dr. Cole and Dr. Karol had no relevant financial disclosures.
On Twitter @maryjodales
ORLANDO – Variants in mesenchymal stem cell genes that are important to bone and fat differentiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukemia, Dr. Seth E. Karol, of St. Jude Children’s Research Hospital in Memphis, reported at the annual meeting of the American Society of Hematology.
In a second study of children with ALL, Dr. Peter D. Cole, of Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture.
The pathophysiology of bony morbidity differs depending on the patient’s age, Dr. Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.”
Bony morbidity is more common in children over age 10 with ALL, and related to exposure to crucial components of leukemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10-20 years old.
However, children under 10 make up 75% of new pediatric ALL diagnoses, Dr. Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases.
In Dr. Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.
The research targeted common variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diagnosis, race, final risk group, and asparaginase randomization. Blood was collected during treatment for analysis of serum and RBC folate.
Of the 637 patients tested, 627 achieved a complete remission and received post-induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures.
Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thymidylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes.
Among children over age 10, this polymorphism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13-3.99; P=0.019).
Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or RBC folate at any time point during therapy.
In the study reported by Dr. Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol.
Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Genes associated with the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways.
Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data.
Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways.
“Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3-6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr. Karol reported.
Dr. Cole and Dr. Karol had no relevant financial disclosures.
On Twitter @maryjodales
AT ASH 2015
Key clinical point: Gene profiles can identify ALL patients under age 10 at increased risk for avascular necrosis.
Major finding: In children under 10 who were homozygous for the 2R polymorphism in thymidylate synthase the rate of 5-year estimated incidence of avascular necrosis was nearly 12%, three times higher than the 4% rate seen in children with 2R/3R or 3R/3R genotypes.
Data source: Research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL.
Disclosures: Dr. Cole and Dr. Karol had no relevant financial disclosures.
ASH: Genes, induction response identify high risk childhood B-lymphoblastic leukemia patients with good outcomes
ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).
Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.
The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.
The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.
After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.
Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.
Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.
Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.
The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.
In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.
Dr. Raetz had no relevant financial disclosures.
Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).
On Twitter @maryjodales
ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).
Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.
The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.
The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.
After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.
Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.
Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.
Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.
The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.
In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.
Dr. Raetz had no relevant financial disclosures.
Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).
On Twitter @maryjodales
ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).
Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.
The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.
The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.
After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.
Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.
Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.
Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.
The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.
In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.
Dr. Raetz had no relevant financial disclosures.
Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).
On Twitter @maryjodales
AT ASH 2015
Key clinical point: Knowing which patients would not benefit from further intensification of their chemotherapy might spare them possible toxicity and late effects.
Major finding: The 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 year EFS of 94% and OS of 98%.
Data source: 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study.
Disclosures: Dr. Raetz had no relevant financial disclosures.
Multiple myeloma advances will be a hot topic at ASH
With the approvals of three new therapies for multiple myeloma in just the last month – elotuzumab, ixazomib, and daratumumab – sessions at ASH 2015 will be buzzing with discussions of how the availability of these new therapies is likely to influence disease management. Other leading abstracts, highlighted at a press conference prior to the annual meeting of the American Society of Hematology, address gene therapy, precision medicine, and stem cell transplant for sickle cell disease. We’re providing the links to these top abstracts here, and invite you to look for our upcoming daily newsletters and next-best-thing-to-being-there coverage of ASH.
Experimental, targeted treatments for blood cancer
• 507: Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase I/II Study (GEN503).
• 727: Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase III Tourmaline-MM1 Study (NCT01564537).
• 391: Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial).
• 495: Results from the International, Randomized Phase III Study of Ibrutinib Versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM).
Experimental gene therapy
• 201: Update of Results from the Northstar Study (HGB-204): A Phase I/II Study of Gene Therapy for Beta-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin BB305 Drug Product).
• 261: Lentiviral Hematopoietic Stem Cell Gene Therapy for Older Patients with X-Linked Severe Combined Immunodeficiency.
Precision medicine
• 250: Genetic Risk Factors for the Development of Osteonecrosis in Children Under Age 10 Treated for Acute Lymphoblastic Leukemia.
• Special Scientific Symposium: Precision Medicine in Cancer Therapy.
Coagulation
• 5: Source of Factor VIII Replacement (PLASMATIC OR RECOMBINANT) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia a: The Multicenter Randomized Sippet Study.
New sickle cell disease research
•541: Hematopoietic Stem Cell Transplantation from HLA Identical Sibling For Sickle Cell Disease an International Survey on Behalf of Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR.
With the approvals of three new therapies for multiple myeloma in just the last month – elotuzumab, ixazomib, and daratumumab – sessions at ASH 2015 will be buzzing with discussions of how the availability of these new therapies is likely to influence disease management. Other leading abstracts, highlighted at a press conference prior to the annual meeting of the American Society of Hematology, address gene therapy, precision medicine, and stem cell transplant for sickle cell disease. We’re providing the links to these top abstracts here, and invite you to look for our upcoming daily newsletters and next-best-thing-to-being-there coverage of ASH.
Experimental, targeted treatments for blood cancer
• 507: Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase I/II Study (GEN503).
• 727: Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase III Tourmaline-MM1 Study (NCT01564537).
• 391: Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial).
• 495: Results from the International, Randomized Phase III Study of Ibrutinib Versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM).
Experimental gene therapy
• 201: Update of Results from the Northstar Study (HGB-204): A Phase I/II Study of Gene Therapy for Beta-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin BB305 Drug Product).
• 261: Lentiviral Hematopoietic Stem Cell Gene Therapy for Older Patients with X-Linked Severe Combined Immunodeficiency.
Precision medicine
• 250: Genetic Risk Factors for the Development of Osteonecrosis in Children Under Age 10 Treated for Acute Lymphoblastic Leukemia.
• Special Scientific Symposium: Precision Medicine in Cancer Therapy.
Coagulation
• 5: Source of Factor VIII Replacement (PLASMATIC OR RECOMBINANT) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia a: The Multicenter Randomized Sippet Study.
New sickle cell disease research
•541: Hematopoietic Stem Cell Transplantation from HLA Identical Sibling For Sickle Cell Disease an International Survey on Behalf of Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR.
With the approvals of three new therapies for multiple myeloma in just the last month – elotuzumab, ixazomib, and daratumumab – sessions at ASH 2015 will be buzzing with discussions of how the availability of these new therapies is likely to influence disease management. Other leading abstracts, highlighted at a press conference prior to the annual meeting of the American Society of Hematology, address gene therapy, precision medicine, and stem cell transplant for sickle cell disease. We’re providing the links to these top abstracts here, and invite you to look for our upcoming daily newsletters and next-best-thing-to-being-there coverage of ASH.
Experimental, targeted treatments for blood cancer
• 507: Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase I/II Study (GEN503).
• 727: Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase III Tourmaline-MM1 Study (NCT01564537).
• 391: Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial).
• 495: Results from the International, Randomized Phase III Study of Ibrutinib Versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM).
Experimental gene therapy
• 201: Update of Results from the Northstar Study (HGB-204): A Phase I/II Study of Gene Therapy for Beta-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin BB305 Drug Product).
• 261: Lentiviral Hematopoietic Stem Cell Gene Therapy for Older Patients with X-Linked Severe Combined Immunodeficiency.
Precision medicine
• 250: Genetic Risk Factors for the Development of Osteonecrosis in Children Under Age 10 Treated for Acute Lymphoblastic Leukemia.
• Special Scientific Symposium: Precision Medicine in Cancer Therapy.
Coagulation
• 5: Source of Factor VIII Replacement (PLASMATIC OR RECOMBINANT) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia a: The Multicenter Randomized Sippet Study.
New sickle cell disease research
•541: Hematopoietic Stem Cell Transplantation from HLA Identical Sibling For Sickle Cell Disease an International Survey on Behalf of Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR.
FROM ASH 2015
Expert panel issues guidelines for treatment of hematologic cancers in pregnancy
Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.
The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).
While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.
“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.
Hodgkin lymphoma
The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.
“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”
Non-Hodgkin lymphoma
The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.
Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).
Chronic myeloid leukemia
Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 109/L and a platelet count greater than 500 X 109/L.
Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.
Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 109/L.
Myeloproliferative neoplasms
The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.
“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.
Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.
In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.
Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.
In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 109/L and hematocrit within appropriate range.
Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.
Acute leukemia
“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.
Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.
When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.
Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.
Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.
The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.
Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.
On Twitter @maryjodales
Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.
The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).
While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.
“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.
Hodgkin lymphoma
The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.
“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”
Non-Hodgkin lymphoma
The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.
Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).
Chronic myeloid leukemia
Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 109/L and a platelet count greater than 500 X 109/L.
Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.
Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 109/L.
Myeloproliferative neoplasms
The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.
“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.
Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.
In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.
Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.
In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 109/L and hematocrit within appropriate range.
Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.
Acute leukemia
“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.
Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.
When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.
Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.
Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.
The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.
Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.
On Twitter @maryjodales
Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.
The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).
While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.
“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.
Hodgkin lymphoma
The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.
“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”
Non-Hodgkin lymphoma
The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.
Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).
Chronic myeloid leukemia
Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 109/L and a platelet count greater than 500 X 109/L.
Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.
Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 109/L.
Myeloproliferative neoplasms
The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.
“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.
Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.
In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.
Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.
In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 109/L and hematocrit within appropriate range.
Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.
Acute leukemia
“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.
Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.
When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.
Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.
Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.
The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.
Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.
On Twitter @maryjodales
FROM JOURNAL OF CLINICAL ONCOLOGY
FDA approves mepolizumab for use in combination with other asthma drugs
Nucala (mepolizumab) has been approved for use with other asthma medicines as maintenance therapy for patients aged 12 years and older with a history of asthma exacerbations despite adherence with their current asthma medicines, the U.S. Food and Drug Administration announced Nov. 4.
“This approval offers patients with severe asthma an additional therapy when current treatments cannot maintain adequate control of their asthma,” Dr. Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.
Nucala is a humanized interleukin-5 antagonist monoclonal antibody that limits severe asthma attacks by reducing the levels of blood eosinophils. Nucala is administered subcutaneously once every 4 weeks by a health care professional.
This innovation in precision medicine is the first and only approved, biologic therapy specifically developed for people with severe asthma with an eosinophilic phenotype, according to a statement from GlaxoSmithKline, the maker of Nucala.
The safety and efficacy of Nucala were established in three double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Nucala or a placebo was administered to patients every 4 weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Nucala had fewer exacerbations requiring hospitalization or emergency department visits, and a longer time to their first exacerbation. In addition, patients with severe asthma receiving Nucala experienced greater reductions in their daily maintenance oral corticosteroid dose, while maintaining asthma control, compared with patients receiving placebo. Treatment with mepolizumab did not result in a significant improvement in lung function, as measured by the volume of air exhaled by patients in 1 second, the FDA said in their statement.
The most common side effects of Nucala include headache, injection site reactions, back pain, and weakness. Hypersensitivity reactions can occur within hours or days of receiving Nucala.
Nucala (mepolizumab) has been approved for use with other asthma medicines as maintenance therapy for patients aged 12 years and older with a history of asthma exacerbations despite adherence with their current asthma medicines, the U.S. Food and Drug Administration announced Nov. 4.
“This approval offers patients with severe asthma an additional therapy when current treatments cannot maintain adequate control of their asthma,” Dr. Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.
Nucala is a humanized interleukin-5 antagonist monoclonal antibody that limits severe asthma attacks by reducing the levels of blood eosinophils. Nucala is administered subcutaneously once every 4 weeks by a health care professional.
This innovation in precision medicine is the first and only approved, biologic therapy specifically developed for people with severe asthma with an eosinophilic phenotype, according to a statement from GlaxoSmithKline, the maker of Nucala.
The safety and efficacy of Nucala were established in three double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Nucala or a placebo was administered to patients every 4 weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Nucala had fewer exacerbations requiring hospitalization or emergency department visits, and a longer time to their first exacerbation. In addition, patients with severe asthma receiving Nucala experienced greater reductions in their daily maintenance oral corticosteroid dose, while maintaining asthma control, compared with patients receiving placebo. Treatment with mepolizumab did not result in a significant improvement in lung function, as measured by the volume of air exhaled by patients in 1 second, the FDA said in their statement.
The most common side effects of Nucala include headache, injection site reactions, back pain, and weakness. Hypersensitivity reactions can occur within hours or days of receiving Nucala.
Nucala (mepolizumab) has been approved for use with other asthma medicines as maintenance therapy for patients aged 12 years and older with a history of asthma exacerbations despite adherence with their current asthma medicines, the U.S. Food and Drug Administration announced Nov. 4.
“This approval offers patients with severe asthma an additional therapy when current treatments cannot maintain adequate control of their asthma,” Dr. Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.
Nucala is a humanized interleukin-5 antagonist monoclonal antibody that limits severe asthma attacks by reducing the levels of blood eosinophils. Nucala is administered subcutaneously once every 4 weeks by a health care professional.
This innovation in precision medicine is the first and only approved, biologic therapy specifically developed for people with severe asthma with an eosinophilic phenotype, according to a statement from GlaxoSmithKline, the maker of Nucala.
The safety and efficacy of Nucala were established in three double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Nucala or a placebo was administered to patients every 4 weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Nucala had fewer exacerbations requiring hospitalization or emergency department visits, and a longer time to their first exacerbation. In addition, patients with severe asthma receiving Nucala experienced greater reductions in their daily maintenance oral corticosteroid dose, while maintaining asthma control, compared with patients receiving placebo. Treatment with mepolizumab did not result in a significant improvement in lung function, as measured by the volume of air exhaled by patients in 1 second, the FDA said in their statement.
The most common side effects of Nucala include headache, injection site reactions, back pain, and weakness. Hypersensitivity reactions can occur within hours or days of receiving Nucala.
Heme Themes: Transplant timing for myelofibrosis in the era of JAK2 inhibitors
ALEXANDRIA, VA. – How are mutation analysis gene panels affecting risk stratification and decision making regarding stem cell transplants in myelofibrosis patients? How are the results of the Dynamic International Prognostic Scoring System (DIPSS) and performance status improvements seen with JAK2 inhibitors influencing who is a candidate for transplant and the timing of transplants?
Watch the conversation between Dr. Vikas Gupta of the leukemia and bone marrow transplant programs at the Princess Margaret Cancer Centre, Toronto, and associate professor of medicine at the University of Toronto, and Dr. Rami S. Komrokji of the Moffitt Cancer Center, Tampa, Fla., as they discuss their individual approaches that consider patient wishes and goals, type of donor, and disease risk in their decisions to perform stem cell transplants upfront or to delay them until after JAK2 inhibitor therapy.
Have an insight to share? Post a comment.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ALEXANDRIA, VA. – How are mutation analysis gene panels affecting risk stratification and decision making regarding stem cell transplants in myelofibrosis patients? How are the results of the Dynamic International Prognostic Scoring System (DIPSS) and performance status improvements seen with JAK2 inhibitors influencing who is a candidate for transplant and the timing of transplants?
Watch the conversation between Dr. Vikas Gupta of the leukemia and bone marrow transplant programs at the Princess Margaret Cancer Centre, Toronto, and associate professor of medicine at the University of Toronto, and Dr. Rami S. Komrokji of the Moffitt Cancer Center, Tampa, Fla., as they discuss their individual approaches that consider patient wishes and goals, type of donor, and disease risk in their decisions to perform stem cell transplants upfront or to delay them until after JAK2 inhibitor therapy.
Have an insight to share? Post a comment.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ALEXANDRIA, VA. – How are mutation analysis gene panels affecting risk stratification and decision making regarding stem cell transplants in myelofibrosis patients? How are the results of the Dynamic International Prognostic Scoring System (DIPSS) and performance status improvements seen with JAK2 inhibitors influencing who is a candidate for transplant and the timing of transplants?
Watch the conversation between Dr. Vikas Gupta of the leukemia and bone marrow transplant programs at the Princess Margaret Cancer Centre, Toronto, and associate professor of medicine at the University of Toronto, and Dr. Rami S. Komrokji of the Moffitt Cancer Center, Tampa, Fla., as they discuss their individual approaches that consider patient wishes and goals, type of donor, and disease risk in their decisions to perform stem cell transplants upfront or to delay them until after JAK2 inhibitor therapy.
Have an insight to share? Post a comment.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT U.S. FOCUS ON MPN AND MDS
Heme Themes: Challenges in averting the progression of MPN, MDS
ALEXANDRIA, VA. – What are the emerging combination therapies for slowing disease progression and improving therapeutic tolerability in myeloproliferative neoplasms and myelodysplastic syndromes?
Join Dr. Jaroslaw Maciejewski, chairman of the department of translational hematology and oncology research at the Taussig Cancer Institute, Cleveland Clinic, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Dr. Ruben A. Mesa, chair of the Division of Hematology/Oncology, department of internal medicine, Mayo Clinic, Scottsdale, Arizona, for their one-on-one discussion of emerging treatment approaches. Then join the conversation by posting your comments and recommendations for other Heme Themes.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ALEXANDRIA, VA. – What are the emerging combination therapies for slowing disease progression and improving therapeutic tolerability in myeloproliferative neoplasms and myelodysplastic syndromes?
Join Dr. Jaroslaw Maciejewski, chairman of the department of translational hematology and oncology research at the Taussig Cancer Institute, Cleveland Clinic, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Dr. Ruben A. Mesa, chair of the Division of Hematology/Oncology, department of internal medicine, Mayo Clinic, Scottsdale, Arizona, for their one-on-one discussion of emerging treatment approaches. Then join the conversation by posting your comments and recommendations for other Heme Themes.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ALEXANDRIA, VA. – What are the emerging combination therapies for slowing disease progression and improving therapeutic tolerability in myeloproliferative neoplasms and myelodysplastic syndromes?
Join Dr. Jaroslaw Maciejewski, chairman of the department of translational hematology and oncology research at the Taussig Cancer Institute, Cleveland Clinic, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Dr. Ruben A. Mesa, chair of the Division of Hematology/Oncology, department of internal medicine, Mayo Clinic, Scottsdale, Arizona, for their one-on-one discussion of emerging treatment approaches. Then join the conversation by posting your comments and recommendations for other Heme Themes.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM U.S. FOCUS ON MPN & MDS
The LAST Study: CML trial examines life after TKIs
In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.
Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.
All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.
Click here to learn more about The LAST Study.
In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.
Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.
All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.
Click here to learn more about The LAST Study.
In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.
Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.
All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.
Click here to learn more about The LAST Study.
FROM CLINICALTRIALS.GOV
Morphine synthesis finding paves way for new painkillers
Researchers have found a gene that is involved in the morphine-producing pathway of poppies.
The finding completes the biosynthetic pathway to morphine, allowing investigations of microbial-based approaches to developing opiate-based pain relievers.
By studying mutations in the poppy plant Papaver somniferum, Thilo Winzer and his colleagues at the University of York, England, discovered that the STORR enzyme, expressed by a gene of the same name, converts (S)-reticuline to an amine, known as 1,2-dehydroreticuline, and that intermediate substrate is then converted to (R)-reticuline. The STORR enzyme contains a cytochrome P450 module, which facilitates the first step of the process, along with oxidoreductase modules that facilitate the second step, according to the researchers, whose collaborators include researchers at GlaxoSmithKline in Boronia, VIC, Australia.
The discovery is one more step in recent efforts to engineer the morphine biosynthesis pathway in yeast, paving the way for cheaper ways to produce painkillers that don’t rely on cultivating poppy fields.
Click here to read the study at Science.
Researchers have found a gene that is involved in the morphine-producing pathway of poppies.
The finding completes the biosynthetic pathway to morphine, allowing investigations of microbial-based approaches to developing opiate-based pain relievers.
By studying mutations in the poppy plant Papaver somniferum, Thilo Winzer and his colleagues at the University of York, England, discovered that the STORR enzyme, expressed by a gene of the same name, converts (S)-reticuline to an amine, known as 1,2-dehydroreticuline, and that intermediate substrate is then converted to (R)-reticuline. The STORR enzyme contains a cytochrome P450 module, which facilitates the first step of the process, along with oxidoreductase modules that facilitate the second step, according to the researchers, whose collaborators include researchers at GlaxoSmithKline in Boronia, VIC, Australia.
The discovery is one more step in recent efforts to engineer the morphine biosynthesis pathway in yeast, paving the way for cheaper ways to produce painkillers that don’t rely on cultivating poppy fields.
Click here to read the study at Science.
Researchers have found a gene that is involved in the morphine-producing pathway of poppies.
The finding completes the biosynthetic pathway to morphine, allowing investigations of microbial-based approaches to developing opiate-based pain relievers.
By studying mutations in the poppy plant Papaver somniferum, Thilo Winzer and his colleagues at the University of York, England, discovered that the STORR enzyme, expressed by a gene of the same name, converts (S)-reticuline to an amine, known as 1,2-dehydroreticuline, and that intermediate substrate is then converted to (R)-reticuline. The STORR enzyme contains a cytochrome P450 module, which facilitates the first step of the process, along with oxidoreductase modules that facilitate the second step, according to the researchers, whose collaborators include researchers at GlaxoSmithKline in Boronia, VIC, Australia.
The discovery is one more step in recent efforts to engineer the morphine biosynthesis pathway in yeast, paving the way for cheaper ways to produce painkillers that don’t rely on cultivating poppy fields.
Click here to read the study at Science.
FROM SCIENCE
VIDEO: AGA Center for GI Innovation and Technology is a supply chain referee
SAN FRANCISCO – Adopting a new GI device means getting it passed through a supply chain at a clinic or a hospital committee. With increasing health care consolidation, it has become harder for new technology to get a foothold. The AGA Center for GI Innovation and Technology can work with manufacturers, physicians, or a facility to help manage the process of pushing a new product along the supply chain. Dr. Joel V. Brill, who serves on the executive committee for the center, explains in this video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN FRANCISCO – Adopting a new GI device means getting it passed through a supply chain at a clinic or a hospital committee. With increasing health care consolidation, it has become harder for new technology to get a foothold. The AGA Center for GI Innovation and Technology can work with manufacturers, physicians, or a facility to help manage the process of pushing a new product along the supply chain. Dr. Joel V. Brill, who serves on the executive committee for the center, explains in this video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN FRANCISCO – Adopting a new GI device means getting it passed through a supply chain at a clinic or a hospital committee. With increasing health care consolidation, it has become harder for new technology to get a foothold. The AGA Center for GI Innovation and Technology can work with manufacturers, physicians, or a facility to help manage the process of pushing a new product along the supply chain. Dr. Joel V. Brill, who serves on the executive committee for the center, explains in this video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE 2015 AGA TECH SUMMIT
