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System could enable oral treatment of hemophilia, team says
Photo courtesy of the CDC
Researchers say they have developed biodegradable hydrophilic carriers that could provide oral delivery of factor IX (FIX) to treat hemophilia B.
Preclinical experiments have shown these carriers can be loaded with FIX and release it in response to environmental
stimuli.
Sarena Horava, PhD, of Triton Systems, Inc. in Chelmsford, Massachusetts, and her colleagues described the carriers in the International Journal of Pharmaceutics.
The current work builds on a previous delivery system devised by Dr Horova and Nicholas A. Peppas, ScD, of The University of Texas at Austin.
Although that system was successful in transporting FIX, the researchers found that modifications were needed to improve the oral bioavailability of FIX.
The team noted that FIX is delicate and unstable in the body’s various pH environments. So the new system is designed to capitalize on the body’s pH and changes in enzymes inside the gastrointestinal tract.
Specifically, the researchers developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)].
The team said the incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine.
The carrier is designed to remain intact as it moves through the body. Once it reaches the small intestine, the carrier should begin to swell with the increase in pH. The carrier should then be degraded by trypsin and slowly release FIX over time.
The researchers said their experiments confirmed that the peptide crosslinked P(MAA-g-EG) microparticles are capable of loading FIX and releasing it under intestinal conditions.
They said the biodegradable component allowed for increased levels of FIX to be released, when compared to the previous system.
Furthermore, both the microparticles and the degradation products enhanced the in vitro absorption of FIX.
“Based on the current capabilities of this system, approximately 2 capsules would be equivalent to 1 injection [of FIX],” Dr Horava said. “However, we anticipate that we will make further improvements to the delivery capacity of the oral delivery system and therefore decrease the capsule amount.”
The researchers plan to conduct additional preclinical experiments with this system before starting clinical trials. 
Photo courtesy of the CDC
Researchers say they have developed biodegradable hydrophilic carriers that could provide oral delivery of factor IX (FIX) to treat hemophilia B.
Preclinical experiments have shown these carriers can be loaded with FIX and release it in response to environmental
stimuli.
Sarena Horava, PhD, of Triton Systems, Inc. in Chelmsford, Massachusetts, and her colleagues described the carriers in the International Journal of Pharmaceutics.
The current work builds on a previous delivery system devised by Dr Horova and Nicholas A. Peppas, ScD, of The University of Texas at Austin.
Although that system was successful in transporting FIX, the researchers found that modifications were needed to improve the oral bioavailability of FIX.
The team noted that FIX is delicate and unstable in the body’s various pH environments. So the new system is designed to capitalize on the body’s pH and changes in enzymes inside the gastrointestinal tract.
Specifically, the researchers developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)].
The team said the incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine.
The carrier is designed to remain intact as it moves through the body. Once it reaches the small intestine, the carrier should begin to swell with the increase in pH. The carrier should then be degraded by trypsin and slowly release FIX over time.
The researchers said their experiments confirmed that the peptide crosslinked P(MAA-g-EG) microparticles are capable of loading FIX and releasing it under intestinal conditions.
They said the biodegradable component allowed for increased levels of FIX to be released, when compared to the previous system.
Furthermore, both the microparticles and the degradation products enhanced the in vitro absorption of FIX.
“Based on the current capabilities of this system, approximately 2 capsules would be equivalent to 1 injection [of FIX],” Dr Horava said. “However, we anticipate that we will make further improvements to the delivery capacity of the oral delivery system and therefore decrease the capsule amount.”
The researchers plan to conduct additional preclinical experiments with this system before starting clinical trials.
Photo courtesy of the CDC
Researchers say they have developed biodegradable hydrophilic carriers that could provide oral delivery of factor IX (FIX) to treat hemophilia B.
Preclinical experiments have shown these carriers can be loaded with FIX and release it in response to environmental
stimuli.
Sarena Horava, PhD, of Triton Systems, Inc. in Chelmsford, Massachusetts, and her colleagues described the carriers in the International Journal of Pharmaceutics.
The current work builds on a previous delivery system devised by Dr Horova and Nicholas A. Peppas, ScD, of The University of Texas at Austin.
Although that system was successful in transporting FIX, the researchers found that modifications were needed to improve the oral bioavailability of FIX.
The team noted that FIX is delicate and unstable in the body’s various pH environments. So the new system is designed to capitalize on the body’s pH and changes in enzymes inside the gastrointestinal tract.
Specifically, the researchers developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)].
The team said the incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine.
The carrier is designed to remain intact as it moves through the body. Once it reaches the small intestine, the carrier should begin to swell with the increase in pH. The carrier should then be degraded by trypsin and slowly release FIX over time.
The researchers said their experiments confirmed that the peptide crosslinked P(MAA-g-EG) microparticles are capable of loading FIX and releasing it under intestinal conditions.
They said the biodegradable component allowed for increased levels of FIX to be released, when compared to the previous system.
Furthermore, both the microparticles and the degradation products enhanced the in vitro absorption of FIX.
“Based on the current capabilities of this system, approximately 2 capsules would be equivalent to 1 injection [of FIX],” Dr Horava said. “However, we anticipate that we will make further improvements to the delivery capacity of the oral delivery system and therefore decrease the capsule amount.”
The researchers plan to conduct additional preclinical experiments with this system before starting clinical trials.
FDA grants full approval for ponatinib
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.
Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.
Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.
Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.
This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.
The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.
“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.
“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”
Past problems with ponatinib
Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.
Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.
Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.
Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.
This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.
The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.
“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.
“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”
Past problems with ponatinib
Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.
Photo from Business Wire
The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.
Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.
Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.
Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.
This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.
The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.
“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.
“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”
Past problems with ponatinib
Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.
EC grants ixazomib conditional approval to treat MM
The European Commission (EC) has granted conditional marketing authorization for ixazomib (NinlaroTM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.
“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.
Phase 3 trial
The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.
Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).
At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.
The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
The European Commission (EC) has granted conditional marketing authorization for ixazomib (NinlaroTM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.
“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.
Phase 3 trial
The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.
Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).
At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.
The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
The European Commission (EC) has granted conditional marketing authorization for ixazomib (NinlaroTM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.
“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.
Phase 3 trial
The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.
Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).
At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.
The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
Decitabine produces responses in high-risk MDS, AML
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
Tazemetostat receives fast track designation for DLBCL
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
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 FDA’s 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 biologic license application or new drug 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.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
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 FDA’s 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 biologic license application or new drug 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.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
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 FDA’s 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 biologic license application or new drug 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.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
AEs from anticoagulants common cause of ED visits
caring for a patient
Photo by Tom Watanabe
A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.
The drug class most often implicated in ED visits was anticoagulants.
Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.
Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.
The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.
The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.
Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.
Results by drug class
The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).
Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.
Results by age
Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).
Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).
Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).
Changes over time
Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.
Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.
An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.
However, the population rates for other age groups were similar for both time periods.
Anticoagulants and antiplatelet agents
Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.
Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).
Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.
Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).
Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.
caring for a patient
Photo by Tom Watanabe
A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.
The drug class most often implicated in ED visits was anticoagulants.
Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.
Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.
The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.
The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.
Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.
Results by drug class
The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).
Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.
Results by age
Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).
Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).
Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).
Changes over time
Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.
Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.
An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.
However, the population rates for other age groups were similar for both time periods.
Anticoagulants and antiplatelet agents
Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.
Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).
Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.
Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).
Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.
caring for a patient
Photo by Tom Watanabe
A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.
The drug class most often implicated in ED visits was anticoagulants.
Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.
Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.
The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.
The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.
Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.
Results by drug class
The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).
Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.
Results by age
Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).
Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).
Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).
Changes over time
Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.
Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.
An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.
However, the population rates for other age groups were similar for both time periods.
Anticoagulants and antiplatelet agents
Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.
Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).
Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.
Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).
Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.
Sex-discordant transfusions don’t increase death risk
Photo by Elise Amendola
There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.
Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.
However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.
The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.
“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”
Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.
To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.
All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.
The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.
Results
The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.
However, there were no other significant differences between the sex-discordant and same-sex groups.
The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.
However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.
The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.
Photo by Elise Amendola
There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.
Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.
However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.
The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.
“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”
Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.
To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.
All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.
The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.
Results
The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.
However, there were no other significant differences between the sex-discordant and same-sex groups.
The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.
However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.
The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.
Photo by Elise Amendola
There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.
Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.
However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.
The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.
“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.
“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”
Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.
To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.
All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.
The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.
Results
The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.
However, there were no other significant differences between the sex-discordant and same-sex groups.
The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.
However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.
The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.
EC grants drug orphan designation for PNH
The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.
Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.
RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.
RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.
According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.
The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.
Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.
RA101495’s orphan designation
The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.
In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.
Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.
The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.
Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.
RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.
RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.
According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.
The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.
Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.
RA101495’s orphan designation
The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.
In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.
Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.
The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.
Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.
RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.
RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.
According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.
The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.
Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.
RA101495’s orphan designation
The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.
In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.
Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.
CAR T-cell trial placed on hold again
Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.
In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.
A total of 5 patients have died of cerebral edema in this trial.
Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.
The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.
Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.
Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.
In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.
Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.
Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.
Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.
Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.
ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.
In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.
A total of 5 patients have died of cerebral edema in this trial.
Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.
The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.
Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.
Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.
In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.
Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.
Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.
Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.
Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.
ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.
In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.
A total of 5 patients have died of cerebral edema in this trial.
Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.
The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.
Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.
Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.
In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.
Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.
Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.
Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.
Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.
ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
EC grants drug orphan status for AML, sarcoma
The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.
Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.
Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.
About orphan designation
The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.
The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.
Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.
Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.
About orphan designation
The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.
The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.
Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.
Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.
About orphan designation
The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.