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NCCN completes resource on radiation therapy
The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.
This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.
The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.
“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . . to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.
“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”
The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.
NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.
At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.
The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.
For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018. 
The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.
This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.
The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.
“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . . to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.
“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”
The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.
NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.
At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.
The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.
For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.
The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.
This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.
The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.
“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . . to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.
“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”
The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.
NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.
At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.
The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.
For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.
Predicting neurotoxicity after CAR T-cell therapy
Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.
The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.
The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.
Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.
“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”
Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.
So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.
The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.
Neurotoxicity
Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.
Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.
Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).
For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.
The 4 neurotoxicity-related deaths were due to:
- Acute cerebral edema (n=2)
- Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
- Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).
Potential biomarkers
In a univariate analysis, neurotoxicity was significantly more frequent in patients who:
- Had CRS (P<0.0001)
- Received a high CAR T-cell dose (P<0.0001)
- Had pre-existing neurologic comorbidities at baseline (P=0.0059).
In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:
- Had pre-existing neurologic comorbidities (P=0.0023)
- Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
- Received a higher CAR T-cell dose (P=0.0009)
- Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).
The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).
“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.
Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.
Algorithm
The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.
The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:
- Fever of 38.9°C or greater
- Serum levels of IL6 at 16 pg/mL or higher
- Serum levels of MCP1 at 1343.5 pg/mL or higher.
This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.
Funding
This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.
Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.
The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.
Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.
The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.
The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.
Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.
“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”
Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.
So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.
The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.
Neurotoxicity
Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.
Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.
Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).
For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.
The 4 neurotoxicity-related deaths were due to:
- Acute cerebral edema (n=2)
- Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
- Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).
Potential biomarkers
In a univariate analysis, neurotoxicity was significantly more frequent in patients who:
- Had CRS (P<0.0001)
- Received a high CAR T-cell dose (P<0.0001)
- Had pre-existing neurologic comorbidities at baseline (P=0.0059).
In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:
- Had pre-existing neurologic comorbidities (P=0.0023)
- Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
- Received a higher CAR T-cell dose (P=0.0009)
- Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).
The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).
“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.
Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.
Algorithm
The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.
The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:
- Fever of 38.9°C or greater
- Serum levels of IL6 at 16 pg/mL or higher
- Serum levels of MCP1 at 1343.5 pg/mL or higher.
This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.
Funding
This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.
Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.
The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.
Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.
The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.
The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.
Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.
“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”
Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.
So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.
The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.
Neurotoxicity
Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.
Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.
Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).
For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.
The 4 neurotoxicity-related deaths were due to:
- Acute cerebral edema (n=2)
- Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
- Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).
Potential biomarkers
In a univariate analysis, neurotoxicity was significantly more frequent in patients who:
- Had CRS (P<0.0001)
- Received a high CAR T-cell dose (P<0.0001)
- Had pre-existing neurologic comorbidities at baseline (P=0.0059).
In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:
- Had pre-existing neurologic comorbidities (P=0.0023)
- Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
- Received a higher CAR T-cell dose (P=0.0009)
- Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).
The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).
“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.
Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.
Algorithm
The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.
The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:
- Fever of 38.9°C or greater
- Serum levels of IL6 at 16 pg/mL or higher
- Serum levels of MCP1 at 1343.5 pg/mL or higher.
This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.
Funding
This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.
Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.
The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.
FDA grants drug fast track designation for rel/ref AML
The US Food and Drug Administration (FDA) has granted fast track designation to gilteritinib for the treatment of adults with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is a compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain, 2 mutations that are seen in approximately one-third of patients with AML.
Gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.
The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.
Researchers said the drug exhibited potent FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.
The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
Gilteritinib also has orphan drug designation for the treatment of AML.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to gilteritinib for the treatment of adults with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is a compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain, 2 mutations that are seen in approximately one-third of patients with AML.
Gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.
The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.
Researchers said the drug exhibited potent FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.
The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
Gilteritinib also has orphan drug designation for the treatment of AML.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to gilteritinib for the treatment of adults with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is a compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain, 2 mutations that are seen in approximately one-third of patients with AML.
Gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.
The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.
Researchers said the drug exhibited potent FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.
The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
Gilteritinib also has orphan drug designation for the treatment of AML.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Antithrombotic agents linked to hematuria-related complications
New research suggests antithrombotic agents increase the risk of hematuria-related complications in older adults.
The study included more than 2.5 million Canadians over the age of 65.
The subjects had an increased risk of emergency department visits, hospitalizations, and urologic procedures to manage visible hematuria if they had received anticoagulants and/or antiplatelet agents.
Robert K. Nam, MD, of Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and his colleagues reported these findings in JAMA.
The researchers examined rates of hematuria-related complications in 2,518,064 citizens of Ontario who were 66 and older between 2002 and 2014.
In all, 808,897 patients received at least 1 prescription for an antithrombotic agent over the study period. This included apixaban, dabigatran, rivaroxaban, warfarin, aspirin, and “other” antiplatelet agents.
At a median follow-up of 7.3 years, the incidence density rates (per 1000 person-years) of hematuria-related complications were 123.95 events among patients who were exposed to antithrombotic agents and 80.17 events among patients who were not (difference=43.8; 95% CI, 43.0-44.6; P<0.001; incidence rate ratio [IRR]=1.44; 95% CI, 1.42-1.46).
The incidence density rates of emergency department visits were 7.05 and 2.51, respectively (difference=4.5; 95% CI, 4.3-4.7; P<0.001; IRR=2.80; 95% CI, 2.74-2.86).
The incidence density rates of hospitalizations were 11.12 and 5.42, respectively (difference=5.7; 95% CI, 5.5-5.9; P<0.001; IRR=2.03; 95% CI, 2.00-2.06).
And the incidence density rates of urologic procedures were 105.78 and 72.24, respectively (difference=33.5; 95% CI, 32.8-34.3; P<0.001; IRR=1.37; 95% CI, 1.36-1.39).
The association between antithrombotic agents and hematuria-related complications was present for all the antithrombotic agents examined.
The researchers noted that this study had limitations. In particular, the cohort was restricted to patients age 66 and older because of funding eligibility for prescription medications in Ontario. Given the interaction between age and the association of antithrombotic therapies with hematuria-related complications, these results are not directly applicable to younger patients.
New research suggests antithrombotic agents increase the risk of hematuria-related complications in older adults.
The study included more than 2.5 million Canadians over the age of 65.
The subjects had an increased risk of emergency department visits, hospitalizations, and urologic procedures to manage visible hematuria if they had received anticoagulants and/or antiplatelet agents.
Robert K. Nam, MD, of Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and his colleagues reported these findings in JAMA.
The researchers examined rates of hematuria-related complications in 2,518,064 citizens of Ontario who were 66 and older between 2002 and 2014.
In all, 808,897 patients received at least 1 prescription for an antithrombotic agent over the study period. This included apixaban, dabigatran, rivaroxaban, warfarin, aspirin, and “other” antiplatelet agents.
At a median follow-up of 7.3 years, the incidence density rates (per 1000 person-years) of hematuria-related complications were 123.95 events among patients who were exposed to antithrombotic agents and 80.17 events among patients who were not (difference=43.8; 95% CI, 43.0-44.6; P<0.001; incidence rate ratio [IRR]=1.44; 95% CI, 1.42-1.46).
The incidence density rates of emergency department visits were 7.05 and 2.51, respectively (difference=4.5; 95% CI, 4.3-4.7; P<0.001; IRR=2.80; 95% CI, 2.74-2.86).
The incidence density rates of hospitalizations were 11.12 and 5.42, respectively (difference=5.7; 95% CI, 5.5-5.9; P<0.001; IRR=2.03; 95% CI, 2.00-2.06).
And the incidence density rates of urologic procedures were 105.78 and 72.24, respectively (difference=33.5; 95% CI, 32.8-34.3; P<0.001; IRR=1.37; 95% CI, 1.36-1.39).
The association between antithrombotic agents and hematuria-related complications was present for all the antithrombotic agents examined.
The researchers noted that this study had limitations. In particular, the cohort was restricted to patients age 66 and older because of funding eligibility for prescription medications in Ontario. Given the interaction between age and the association of antithrombotic therapies with hematuria-related complications, these results are not directly applicable to younger patients.
New research suggests antithrombotic agents increase the risk of hematuria-related complications in older adults.
The study included more than 2.5 million Canadians over the age of 65.
The subjects had an increased risk of emergency department visits, hospitalizations, and urologic procedures to manage visible hematuria if they had received anticoagulants and/or antiplatelet agents.
Robert K. Nam, MD, of Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and his colleagues reported these findings in JAMA.
The researchers examined rates of hematuria-related complications in 2,518,064 citizens of Ontario who were 66 and older between 2002 and 2014.
In all, 808,897 patients received at least 1 prescription for an antithrombotic agent over the study period. This included apixaban, dabigatran, rivaroxaban, warfarin, aspirin, and “other” antiplatelet agents.
At a median follow-up of 7.3 years, the incidence density rates (per 1000 person-years) of hematuria-related complications were 123.95 events among patients who were exposed to antithrombotic agents and 80.17 events among patients who were not (difference=43.8; 95% CI, 43.0-44.6; P<0.001; incidence rate ratio [IRR]=1.44; 95% CI, 1.42-1.46).
The incidence density rates of emergency department visits were 7.05 and 2.51, respectively (difference=4.5; 95% CI, 4.3-4.7; P<0.001; IRR=2.80; 95% CI, 2.74-2.86).
The incidence density rates of hospitalizations were 11.12 and 5.42, respectively (difference=5.7; 95% CI, 5.5-5.9; P<0.001; IRR=2.03; 95% CI, 2.00-2.06).
And the incidence density rates of urologic procedures were 105.78 and 72.24, respectively (difference=33.5; 95% CI, 32.8-34.3; P<0.001; IRR=1.37; 95% CI, 1.36-1.39).
The association between antithrombotic agents and hematuria-related complications was present for all the antithrombotic agents examined.
The researchers noted that this study had limitations. In particular, the cohort was restricted to patients age 66 and older because of funding eligibility for prescription medications in Ontario. Given the interaction between age and the association of antithrombotic therapies with hematuria-related complications, these results are not directly applicable to younger patients.
Immunotherapy demonstrates potential for T-cell lymphoma
Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.
The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.
Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.
The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.
Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.
The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.
Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.
The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).
In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.
The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.
3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)
However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.
The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.
Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.
Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.
Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”
The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.
Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.
Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.
Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.
The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.
Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.
The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.
Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.
The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.
Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.
The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).
In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.
The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.
3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)
However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.
The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.
Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.
Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.
Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”
The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.
Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.
Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.
Researchers have reported successful inhibition of the phosphatase SHIP1, which may be an effective approach for treating T-cell lymphoma.
The team found that intermittent treatment with a SHIP1 inhibitor prevented the immune exhaustion observed with SHIP1 deletion.
Intermittent SHIP1 inhibition enhanced the antitumor activity of natural killer (NK) cells and T cells in a mouse model of T-cell lymphoma.
The treatment also appeared to have a direct chemotherapeutic effect and induced immunological memory against lymphoma cells.
Matthew Gumbleton, MD, of SUNY Upstate Medical University in Syracuse, New York, and his colleagues reported these results in Science Signaling.
The researchers noted that previous efforts to inhibit SHIP1 have yielded disappointing results. Mice engineered to lack the SHIP1 gene had poorly responsive immune systems, potentially because overactivated cells became exhausted.
Dr Gumbleton and his colleagues found they could overcome this problem by administering a SHIP1 inhibitor—3-a-aminocholestane (3AC)—in a pulsed regimen of 2 consecutive treatment days per week.
The team tested this regimen in mouse models of colorectal cancer and T-cell lymphoma (RMA-Rae1).
In the lymphoma model, intermittent 3AC treatment increased the responsiveness of T cells and NK cells.
The treatment significantly increased the number of NK cells at the tumor site and the terminal maturation of the peripheral NK-cell compartment.
3AC also enhanced FasL-Fas–mediated killing of lymphoma cells. (NK cells induce apoptosis of target cells via Fas-FasL signaling.)
However, 3AC treatment reduced lymphoma burden in NK-cell-deficient mice as well. Therefore, the researchers believe 3AC may have a direct chemotherapeutic effect.
The team also found that intermittent 3AC treatment increased survival in lymphoma-bearing mice.
Treated mice had significantly longer survival than control mice. And some of the treated mice had long-term survival with no evidence of tumor burden, which suggests the treatment could be curative.
Additional experiments revealed that both NK cells and T cells were required to induce long-term survival in the lymphoma-bearing mice.
Finally, the researchers found evidence to suggest that 3AC treatment triggered “immunological memory capable of sustained and protective antitumor response that prevents relapse.”
The team infused hematolymphoid cells from either a naïve donor mouse or a lymphoma-challenged, 3AC-treated, long-term-surviving donor mouse into naïve host mice. The host mice were then challenged with RMA-Rae1 cells but didn’t receive 3AC.
Mice that received cells from the 3AC-treated donors had significantly better survival than mice that received cells from naive donors.
Based on these results, the researchers concluded that intermittent SHIP1 inhibition may be effective for treating and preventing relapse of T-cell lymphoma and other cancers.
AML trial placed on full clinical hold
The US Food and Drug Administration (FDA) has placed a full clinical hold on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
The hold is due to a fatal cerebral adverse event that is considered possibly related to SEL24.
The clinical hold means no new patients will be enrolled in the trial and enrolled patients will not receive SEL24 until the hold is lifted.
Selvita S.A., the company developing SEL24, received a clinical hold letter from the FDA on October 6 and said it plans to work with the agency to have the hold lifted.
As part of this process, Selvita will provide the FDA with additional data and analysis on patients treated with SEL24 as well as a proposed protocol amendment.
The trial began in the first quarter of 2017. The study is designed to determine the maximum tolerated dose and recommended dose of SEL24 in patients with relapsed and refractory AML. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
One AML patient started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort and received 4 doses of the drug. This patient developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later due to the cerebral event. The patient’s death was subsequently evaluated as possibly related to SEL24.
A safety report and a review of data by the trial’s data monitoring committee were submitted to the FDA. The agency then placed a clinical hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita said it plans to comply with the requests and provide additional information to the agency and clinical trial centers, in collaboration with the Menarini Group, its global development partner for SEL24.
The FDA has 30 days from the receipt of Selvita’s response to let the company know whether the clinical hold is lifted.
The US Food and Drug Administration (FDA) has placed a full clinical hold on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
The hold is due to a fatal cerebral adverse event that is considered possibly related to SEL24.
The clinical hold means no new patients will be enrolled in the trial and enrolled patients will not receive SEL24 until the hold is lifted.
Selvita S.A., the company developing SEL24, received a clinical hold letter from the FDA on October 6 and said it plans to work with the agency to have the hold lifted.
As part of this process, Selvita will provide the FDA with additional data and analysis on patients treated with SEL24 as well as a proposed protocol amendment.
The trial began in the first quarter of 2017. The study is designed to determine the maximum tolerated dose and recommended dose of SEL24 in patients with relapsed and refractory AML. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
One AML patient started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort and received 4 doses of the drug. This patient developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later due to the cerebral event. The patient’s death was subsequently evaluated as possibly related to SEL24.
A safety report and a review of data by the trial’s data monitoring committee were submitted to the FDA. The agency then placed a clinical hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita said it plans to comply with the requests and provide additional information to the agency and clinical trial centers, in collaboration with the Menarini Group, its global development partner for SEL24.
The FDA has 30 days from the receipt of Selvita’s response to let the company know whether the clinical hold is lifted.
The US Food and Drug Administration (FDA) has placed a full clinical hold on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).
The hold is due to a fatal cerebral adverse event that is considered possibly related to SEL24.
The clinical hold means no new patients will be enrolled in the trial and enrolled patients will not receive SEL24 until the hold is lifted.
Selvita S.A., the company developing SEL24, received a clinical hold letter from the FDA on October 6 and said it plans to work with the agency to have the hold lifted.
As part of this process, Selvita will provide the FDA with additional data and analysis on patients treated with SEL24 as well as a proposed protocol amendment.
The trial began in the first quarter of 2017. The study is designed to determine the maximum tolerated dose and recommended dose of SEL24 in patients with relapsed and refractory AML. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.
One AML patient started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort and received 4 doses of the drug. This patient developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.
The patient died in hospice 4 days later due to the cerebral event. The patient’s death was subsequently evaluated as possibly related to SEL24.
A safety report and a review of data by the trial’s data monitoring committee were submitted to the FDA. The agency then placed a clinical hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.
Selvita said it plans to comply with the requests and provide additional information to the agency and clinical trial centers, in collaboration with the Menarini Group, its global development partner for SEL24.
The FDA has 30 days from the receipt of Selvita’s response to let the company know whether the clinical hold is lifted.
FDA rejects pegfilgrastim biosimilar
The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).
Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.
Biocon and Mylan filed the biologics license application for MYL-1401H in February.
The FDA had planned to issue a decision on the application by October 9.
Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.
The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)
Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.
The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).
Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.
Biocon and Mylan filed the biologics license application for MYL-1401H in February.
The FDA had planned to issue a decision on the application by October 9.
Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.
The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)
Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.
The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).
Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.
Biocon and Mylan filed the biologics license application for MYL-1401H in February.
The FDA had planned to issue a decision on the application by October 9.
Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.
The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)
Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.
Team identifies genetic drivers of DLBCL
Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).
Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.
Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.
“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.
“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”
Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.
Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.
The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”
However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.
Essential genes
To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.
This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.
The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.
The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.
In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.
Patient outcomes
The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.
Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.
In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.
Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).
The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.
Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).
Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.
Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.
“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.
“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”
Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.
Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.
The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”
However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.
Essential genes
To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.
This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.
The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.
The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.
In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.
Patient outcomes
The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.
Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.
In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.
Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).
The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.
Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).
Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.
Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.
“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.
“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”
Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.
Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.
The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”
However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.
Essential genes
To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.
This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.
The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.
The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.
In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.
Patient outcomes
The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.
Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.
In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.
Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).
The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.
FDA grants drug orphan designation for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).
PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.
PCM-075 is being developed by Trovagene, Inc.
The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).
Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.
According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.
Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).
PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.
PCM-075 is being developed by Trovagene, Inc.
The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).
Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.
According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.
Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).
PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.
PCM-075 is being developed by Trovagene, Inc.
The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).
Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.
According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.
Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Rivaroxaban trial stopped early due to futility
The companies developing rivaroxaban have announced an early end to the phase 3 NAVIGATE ESUS study.
In this trial, researchers were evaluating the efficacy and safety of rivaroxaban for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source (ESUS).
The study was stopped early after it became evident that rivaroxaban was unlikely to provide a benefit over aspirin.
Results showed comparable efficacy between rivaroxaban and aspirin and an increase in bleeding in the rivaroxaban arm, although bleeding rates were considered low overall.
The NAVIGATE ESUS trial enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to receive either rivaroxaban at 15 mg once daily or aspirin at 100 mg once daily.
The primary efficacy endpoint was a composite of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis.
A complete analysis of NAVIGATE ESUS data is expected to be presented in 2018.
About rivaroxaban
Rivaroxaban was discovered by Bayer, which is developing the drug with Janssen Research & Development, LLC.
Rivaroxaban is approved for use in more than 130 countries for a total of 7 indications:
- The prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and 1 or more risk factors
- The treatment of pulmonary embolism (PE) in adults
- The treatment of deep vein thrombosis (DVT) in adults
- The prevention of recurrent PE and DVT in adults
- The prevention of venous thromboembolism (VTE) in adults undergoing elective hip replacement surgery
- The prevention of VTE in adults undergoing elective knee replacement surgery
- The prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with elevated cardiac biomarkers and no prior stroke or transient ischemic attack when co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.
The companies developing rivaroxaban have announced an early end to the phase 3 NAVIGATE ESUS study.
In this trial, researchers were evaluating the efficacy and safety of rivaroxaban for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source (ESUS).
The study was stopped early after it became evident that rivaroxaban was unlikely to provide a benefit over aspirin.
Results showed comparable efficacy between rivaroxaban and aspirin and an increase in bleeding in the rivaroxaban arm, although bleeding rates were considered low overall.
The NAVIGATE ESUS trial enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to receive either rivaroxaban at 15 mg once daily or aspirin at 100 mg once daily.
The primary efficacy endpoint was a composite of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis.
A complete analysis of NAVIGATE ESUS data is expected to be presented in 2018.
About rivaroxaban
Rivaroxaban was discovered by Bayer, which is developing the drug with Janssen Research & Development, LLC.
Rivaroxaban is approved for use in more than 130 countries for a total of 7 indications:
- The prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and 1 or more risk factors
- The treatment of pulmonary embolism (PE) in adults
- The treatment of deep vein thrombosis (DVT) in adults
- The prevention of recurrent PE and DVT in adults
- The prevention of venous thromboembolism (VTE) in adults undergoing elective hip replacement surgery
- The prevention of VTE in adults undergoing elective knee replacement surgery
- The prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with elevated cardiac biomarkers and no prior stroke or transient ischemic attack when co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.
The companies developing rivaroxaban have announced an early end to the phase 3 NAVIGATE ESUS study.
In this trial, researchers were evaluating the efficacy and safety of rivaroxaban for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source (ESUS).
The study was stopped early after it became evident that rivaroxaban was unlikely to provide a benefit over aspirin.
Results showed comparable efficacy between rivaroxaban and aspirin and an increase in bleeding in the rivaroxaban arm, although bleeding rates were considered low overall.
The NAVIGATE ESUS trial enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to receive either rivaroxaban at 15 mg once daily or aspirin at 100 mg once daily.
The primary efficacy endpoint was a composite of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis.
A complete analysis of NAVIGATE ESUS data is expected to be presented in 2018.
About rivaroxaban
Rivaroxaban was discovered by Bayer, which is developing the drug with Janssen Research & Development, LLC.
Rivaroxaban is approved for use in more than 130 countries for a total of 7 indications:
- The prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and 1 or more risk factors
- The treatment of pulmonary embolism (PE) in adults
- The treatment of deep vein thrombosis (DVT) in adults
- The prevention of recurrent PE and DVT in adults
- The prevention of venous thromboembolism (VTE) in adults undergoing elective hip replacement surgery
- The prevention of VTE in adults undergoing elective knee replacement surgery
- The prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with elevated cardiac biomarkers and no prior stroke or transient ischemic attack when co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.