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Enzyme may be target for MM treatment
The enzyme ADAR1 may be a therapeutic target for multiple myeloma (MM), according to research published in Nature Communications.
Investigators found that high ADAR1 levels correlate with reduced survival rates in MM patients.
The team also discovered that blocking ADAR1 reduced regeneration of high-risk MM in serially transplantable patient-derived xenografts.
The investigators believe that JAK2 inhibitors could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in patients with MM.
“Despite new therapies, it’s virtually inevitable that a patient with multiple myeloma will experience relapse of the disease at some point,” said study author Catriona Jamieson, MD, PhD, of University of California, San Diego, in La Jolla.
“That’s why it’s exciting that this discovery may allow us to detect the disease earlier and address the root cause.”
Dr Jamieson and her colleagues knew that ADAR1 is normally expressed during fetal development to help blood cells form. The enzyme edits the sequence of RNA and is known to promote cancer progression and resistance to therapy.
With previous work, Dr Jamieson’s team described ADAR1’s contributions to chronic myeloid leukemia (CML). The enzyme’s RNA-editing activity boosts leukemic stem cells, giving rise to CML, increasing disease recurrence, and allowing CML to resist treatment.
For their current study, Dr Jamieson and her colleagues investigated ADAR1’s role in MM, first analyzing a database of nearly 800 MM patient samples.
The investigators found that patients with low ADAR1 levels in their tumor cells survived longer than patients with high ADAR1 levels.
While more than 90% of patients with low ADAR1 levels survived longer than 2 years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels did the same.
The investigators also created a humanized mouse model of MM and found that silencing the ADAR1 gene reduced the engraftment of MM.
“This is a difficult disease to model in animals; there isn’t a single gene we can manipulate to mimic multiple myeloma,” said study author Leslie A. Crews, PhD, of University of California, San Diego.
“This study is important, in part because we now have a new xenograft model that will, for the first time, allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
To advance their findings from this study, the investigators are exploring ways to leverage ADAR1 to detect MM progression as early as possible.
They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models.
“Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and, thus, can only reduce the bulk of the tumor,” Dr Jamieson said.
“They don’t get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach ‘precision regenerative medicine.’” 
The enzyme ADAR1 may be a therapeutic target for multiple myeloma (MM), according to research published in Nature Communications.
Investigators found that high ADAR1 levels correlate with reduced survival rates in MM patients.
The team also discovered that blocking ADAR1 reduced regeneration of high-risk MM in serially transplantable patient-derived xenografts.
The investigators believe that JAK2 inhibitors could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in patients with MM.
“Despite new therapies, it’s virtually inevitable that a patient with multiple myeloma will experience relapse of the disease at some point,” said study author Catriona Jamieson, MD, PhD, of University of California, San Diego, in La Jolla.
“That’s why it’s exciting that this discovery may allow us to detect the disease earlier and address the root cause.”
Dr Jamieson and her colleagues knew that ADAR1 is normally expressed during fetal development to help blood cells form. The enzyme edits the sequence of RNA and is known to promote cancer progression and resistance to therapy.
With previous work, Dr Jamieson’s team described ADAR1’s contributions to chronic myeloid leukemia (CML). The enzyme’s RNA-editing activity boosts leukemic stem cells, giving rise to CML, increasing disease recurrence, and allowing CML to resist treatment.
For their current study, Dr Jamieson and her colleagues investigated ADAR1’s role in MM, first analyzing a database of nearly 800 MM patient samples.
The investigators found that patients with low ADAR1 levels in their tumor cells survived longer than patients with high ADAR1 levels.
While more than 90% of patients with low ADAR1 levels survived longer than 2 years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels did the same.
The investigators also created a humanized mouse model of MM and found that silencing the ADAR1 gene reduced the engraftment of MM.
“This is a difficult disease to model in animals; there isn’t a single gene we can manipulate to mimic multiple myeloma,” said study author Leslie A. Crews, PhD, of University of California, San Diego.
“This study is important, in part because we now have a new xenograft model that will, for the first time, allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
To advance their findings from this study, the investigators are exploring ways to leverage ADAR1 to detect MM progression as early as possible.
They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models.
“Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and, thus, can only reduce the bulk of the tumor,” Dr Jamieson said.
“They don’t get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach ‘precision regenerative medicine.’”
The enzyme ADAR1 may be a therapeutic target for multiple myeloma (MM), according to research published in Nature Communications.
Investigators found that high ADAR1 levels correlate with reduced survival rates in MM patients.
The team also discovered that blocking ADAR1 reduced regeneration of high-risk MM in serially transplantable patient-derived xenografts.
The investigators believe that JAK2 inhibitors could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in patients with MM.
“Despite new therapies, it’s virtually inevitable that a patient with multiple myeloma will experience relapse of the disease at some point,” said study author Catriona Jamieson, MD, PhD, of University of California, San Diego, in La Jolla.
“That’s why it’s exciting that this discovery may allow us to detect the disease earlier and address the root cause.”
Dr Jamieson and her colleagues knew that ADAR1 is normally expressed during fetal development to help blood cells form. The enzyme edits the sequence of RNA and is known to promote cancer progression and resistance to therapy.
With previous work, Dr Jamieson’s team described ADAR1’s contributions to chronic myeloid leukemia (CML). The enzyme’s RNA-editing activity boosts leukemic stem cells, giving rise to CML, increasing disease recurrence, and allowing CML to resist treatment.
For their current study, Dr Jamieson and her colleagues investigated ADAR1’s role in MM, first analyzing a database of nearly 800 MM patient samples.
The investigators found that patients with low ADAR1 levels in their tumor cells survived longer than patients with high ADAR1 levels.
While more than 90% of patients with low ADAR1 levels survived longer than 2 years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels did the same.
The investigators also created a humanized mouse model of MM and found that silencing the ADAR1 gene reduced the engraftment of MM.
“This is a difficult disease to model in animals; there isn’t a single gene we can manipulate to mimic multiple myeloma,” said study author Leslie A. Crews, PhD, of University of California, San Diego.
“This study is important, in part because we now have a new xenograft model that will, for the first time, allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
To advance their findings from this study, the investigators are exploring ways to leverage ADAR1 to detect MM progression as early as possible.
They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models.
“Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and, thus, can only reduce the bulk of the tumor,” Dr Jamieson said.
“They don’t get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach ‘precision regenerative medicine.’”
Health Canada approves midostaurin for AML
Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).
This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.
Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.
Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).
And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.
Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).
This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.
Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.
Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).
And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.
Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Health Canada has approved use of the multi-targeted kinase inhibitor midostaurin (Rydapt™).
This makes midostaurin the first targeted therapy approved to treat FLT3-mutated acute myeloid leukemia (AML) in Canada.
Midostaurin is approved for use with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adults with newly diagnosed FLT3-mutated AML.
Health Canada’s approval of midostaurin is based on results from the phase 3 RATIFY trial, which were published in NEJM in August.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).
And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis.
Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Companies launch generic busulfan in US
Two companies have announced the US launch of a generic busulfan product, Myleran Injection.
Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.
The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.
Two companies have announced the US launch of a generic busulfan product, Myleran Injection.
Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.
The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.
Two companies have announced the US launch of a generic busulfan product, Myleran Injection.
Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.
The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.
System helps predict RFS, OS in BCP-ALL
Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.
The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.
The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.
On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).
Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.
The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.
Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.
“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”
“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”
The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”
And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.
The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.
The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.
Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.
“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”
Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.
The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.
The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.
On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).
Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.
The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.
Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.
“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”
“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”
The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”
And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.
The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.
The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.
Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.
“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”
Researchers say they have developed a more accurate risk scoring system for children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are typically thought to have standard- or medium-risk disease.
The scoring system includes 3 factors associated with higher-risk BCP-ALL—the presence of high-risk ALL gene microdeletions, having minimal residual disease (MRD) greater than 5 x 10-5 at day 33, and being high-risk according to National Cancer Institute (NCI) classification.
The researchers found that children with 2 or more of these characteristics were most likely to relapse or die within 7 years of treatment initiation.
On the other hand, children without any of the 3 characteristics had high rates of relapse-free survival (RFS) and overall survival (OS).
Rosemary Sutton, PhD, of Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues devised this risk scoring system and described it in the British Journal of Haematology.
The researchers created their system with the help of data from 475 patients (ages 1 to 18) who had BCP-ALL and were considered non-high-risk. The patients were enrolled on the ANZCHOG ALL8 trial.
Dr Sutton and her colleagues noted that children with standard- or medium-risk BCP-ALL typically receive less intensive treatment than children with high-risk BCP-ALL. However, some of the standard- and medium-risk patients do relapse.
“For the standard- to medium-risk group, we needed more information to get a better handle on the biology of the child’s cancer to better determine their risk,” Dr Sutton said. “So we supplemented MRD results with 2 other pieces of patient information—the presence or absence of specific gene microdeletions and a score called the NCI risk, based on age and white blood cell count.”
“We tested for microdeletions in 9 genes involved in leukemia and found that 2 of the genes—IKZF1 and P2RY8-CRLF2—were important predictors of relapse.”
The researchers combined patients with IKZF1 intragenic deletions, P2RY8-CRLF2 gene fusion, or both into a “high-risk deletion group.”
And the team based the scoring system on 3 factors—the high-risk deletion group, MRD >5 x 10-5 at day 33, and high risk according to NCI risk classification. Patients received 1 point for each of these factors.
The RFS rate was 93% for patients with a score of 0, 78% for those with a score of 1, and 49% for patients with a score of 2 or 3. The OS rate was 99%, 91%, and 71%, respectively.
The researchers said their scoring system provided greater discrimination than MRD-based risk stratification into a standard-risk group—which had an RFS of 89% and an OS of 96%—and a medium-risk group—which had an RFS of 79% and an OS of 91%.
Study author Toby Trahair, MBBS, PhD, of Sydney Children’s Hospital in Randwick, New South Wales, said this scoring system could make a big difference to the success of BCP-ALL treatment.
“We are always trying to improve how we diagnose and treat children with this most common childhood cancer,” Dr Trahair said. “This risk score will mean doctors can fine tune a child’s risk category and so fine tune their treatment. It will mean more kids can conquer this horrible disease, which, only 50 years ago, had survival rates of close to 0.”
FDA approves use of heparin products
The US Food and Drug Administration (FDA) has approved use of Mylan NV’s heparin products.
This includes Heparin Sodium Injection at 1000 USP/mL, 5000 USP/mL, 10,000 USP/mL, and 20,000 USP/mL, all of which are packaged in multi-dose vials.
These products should be available in the coming weeks, according to Rajiv Malik, the president of Mylan.
Mylan’s heparin products are approved for the same uses as other heparin products approved in the US.
This includes as prophylaxis and treatment for venous thrombosis and its extension, pulmonary embolism, and peripheral arterial embolism.
The heparin products can also be used to treat atrial fibrillation with embolization, prevent clotting in arterial and cardiac surgery, and diagnose/treat acute and chronic consumptive coagulopathies (disseminated intravascular coagulation).
Low-dose heparin can be used to prevent post-operative deep vein thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease.
Heparin can also be used as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures, as well as in blood samples for laboratory purposes.
“We are very proud of today’s FDA approval of Heparin Sodium Injection, as this approval adds yet another highly complex and difficult-to-manufacture product to our portfolio,” Malik said.
“We expect to make our heparin products available to US hospitals in the coming weeks, further supporting our institutional customers in meeting the needs of their patients who depend on high-quality anticoagulants.”
The US Food and Drug Administration (FDA) has approved use of Mylan NV’s heparin products.
This includes Heparin Sodium Injection at 1000 USP/mL, 5000 USP/mL, 10,000 USP/mL, and 20,000 USP/mL, all of which are packaged in multi-dose vials.
These products should be available in the coming weeks, according to Rajiv Malik, the president of Mylan.
Mylan’s heparin products are approved for the same uses as other heparin products approved in the US.
This includes as prophylaxis and treatment for venous thrombosis and its extension, pulmonary embolism, and peripheral arterial embolism.
The heparin products can also be used to treat atrial fibrillation with embolization, prevent clotting in arterial and cardiac surgery, and diagnose/treat acute and chronic consumptive coagulopathies (disseminated intravascular coagulation).
Low-dose heparin can be used to prevent post-operative deep vein thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease.
Heparin can also be used as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures, as well as in blood samples for laboratory purposes.
“We are very proud of today’s FDA approval of Heparin Sodium Injection, as this approval adds yet another highly complex and difficult-to-manufacture product to our portfolio,” Malik said.
“We expect to make our heparin products available to US hospitals in the coming weeks, further supporting our institutional customers in meeting the needs of their patients who depend on high-quality anticoagulants.”
The US Food and Drug Administration (FDA) has approved use of Mylan NV’s heparin products.
This includes Heparin Sodium Injection at 1000 USP/mL, 5000 USP/mL, 10,000 USP/mL, and 20,000 USP/mL, all of which are packaged in multi-dose vials.
These products should be available in the coming weeks, according to Rajiv Malik, the president of Mylan.
Mylan’s heparin products are approved for the same uses as other heparin products approved in the US.
This includes as prophylaxis and treatment for venous thrombosis and its extension, pulmonary embolism, and peripheral arterial embolism.
The heparin products can also be used to treat atrial fibrillation with embolization, prevent clotting in arterial and cardiac surgery, and diagnose/treat acute and chronic consumptive coagulopathies (disseminated intravascular coagulation).
Low-dose heparin can be used to prevent post-operative deep vein thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease.
Heparin can also be used as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures, as well as in blood samples for laboratory purposes.
“We are very proud of today’s FDA approval of Heparin Sodium Injection, as this approval adds yet another highly complex and difficult-to-manufacture product to our portfolio,” Malik said.
“We expect to make our heparin products available to US hospitals in the coming weeks, further supporting our institutional customers in meeting the needs of their patients who depend on high-quality anticoagulants.”
Cell-free DNA kit receives CE-IVD mark
Vela Diagnostics’ Sentosa® SX Cell-free DNA (cfDNA) Kit has received the CE-IVD mark, which means this kit is approved for in vitro diagnostics use in the European Union.
The Sentosa® SX cfDNA Kit is intended to extract free-circulating DNA from human plasma.
The kit was developed for use in next-generation sequencing and real-time polymerase chain reaction workflows.
The kit is designed to run on the Sentosa® SX101 instrument and works with whole blood samples collected in Cell-free DNA BCT from Streck, K2, or K3 EDTA tubes.
Automated sample extraction with the Sentosa® SX cfDNA Kit takes approximately 3.5 hours. It requires 20 minutes of operator hands-on time and 4 mL of plasma from the clinical sample.
The Sentosa® SX cfDNA Kit is able to recover low-frequency DNA variants in blood, according to Vela Diagnostics.
Results from a pilot study testing the kit were presented in a poster at the AMP 2016 Annual Meeting.
Vela Diagnostics’ Sentosa® SX Cell-free DNA (cfDNA) Kit has received the CE-IVD mark, which means this kit is approved for in vitro diagnostics use in the European Union.
The Sentosa® SX cfDNA Kit is intended to extract free-circulating DNA from human plasma.
The kit was developed for use in next-generation sequencing and real-time polymerase chain reaction workflows.
The kit is designed to run on the Sentosa® SX101 instrument and works with whole blood samples collected in Cell-free DNA BCT from Streck, K2, or K3 EDTA tubes.
Automated sample extraction with the Sentosa® SX cfDNA Kit takes approximately 3.5 hours. It requires 20 minutes of operator hands-on time and 4 mL of plasma from the clinical sample.
The Sentosa® SX cfDNA Kit is able to recover low-frequency DNA variants in blood, according to Vela Diagnostics.
Results from a pilot study testing the kit were presented in a poster at the AMP 2016 Annual Meeting.
Vela Diagnostics’ Sentosa® SX Cell-free DNA (cfDNA) Kit has received the CE-IVD mark, which means this kit is approved for in vitro diagnostics use in the European Union.
The Sentosa® SX cfDNA Kit is intended to extract free-circulating DNA from human plasma.
The kit was developed for use in next-generation sequencing and real-time polymerase chain reaction workflows.
The kit is designed to run on the Sentosa® SX101 instrument and works with whole blood samples collected in Cell-free DNA BCT from Streck, K2, or K3 EDTA tubes.
Automated sample extraction with the Sentosa® SX cfDNA Kit takes approximately 3.5 hours. It requires 20 minutes of operator hands-on time and 4 mL of plasma from the clinical sample.
The Sentosa® SX cfDNA Kit is able to recover low-frequency DNA variants in blood, according to Vela Diagnostics.
Results from a pilot study testing the kit were presented in a poster at the AMP 2016 Annual Meeting.
Antimalarial could aid treatment of ALL
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
Plek2 may be therapeutic target in MPNs
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
Drug receives fast track designation for FLT3+ rel/ref AML
The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
Crenolanib is being developed by Arog Pharmaceuticals, Inc.
The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.
Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).
The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.
Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.
Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m2 three times a day (n=26).
In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).
In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).
In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).
Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).
Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.
There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.
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.
The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
Crenolanib is being developed by Arog Pharmaceuticals, Inc.
The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.
Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).
The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.
Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.
Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m2 three times a day (n=26).
In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).
In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).
In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).
Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).
Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.
There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.
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.
The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
Crenolanib is being developed by Arog Pharmaceuticals, Inc.
The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.
Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).
The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.
Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.
Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m2 three times a day (n=26).
In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).
In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).
In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).
Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).
Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.
There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.
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.
Combo prolongs survival in lymphoma models
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.