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Gene therapy trial underway in hemophilia B
TORONTO – Researchers may be making some headway in the search for a gene therapy strategy to treat hemophilia B.
Preliminary findings from an ongoing phase 1-2 trial of an investigational gene therapy treatment in patients with hemophilia B were generally positive, based on results from the first seven patients.
Dr. Paul E. Monahan of the University of North Carolina Gene Therapy Center and Lineberger Comprehensive Cancer Center, Chapel Hill, reported that BAX 335 consists of a codon-optimized hyperactive FIX transgene driven by the liver-specific transthyretin (TTR) promoter in a nonintegrating adeno-associated viral (AAV) vector carrying a blood-clotting factor IX (FIX) gene.
The trial, the first in-human study of BAX 335, aims to evaluate the safety and kinetics of this gene therapy candidate. Dr. Monahan presented results from a combined follow-up of nearly 100 months on the first seven subjects, who were given one of three dosing schedules.
The adult male patients had hemophilia B and more than three hemorrhages per year requiring treatment with FIX, plasma FIX activity less than or equal to 2%, and a negative screen for hepatitis C. Patients with a family history of inhibitor to FIX protein or an allergic reaction to any FIX product were excluded, as were those with evidence of hepatic inflammation or cirrhosis.
The results for these seven subjects were generally positive. The BAX 335 doses were Cohort 1 (2 subjects): 1 x 1012 vg kg-1; Cohort 2 (3 subjects): 2 x 1012 vg kg-1; Cohort 3 (2 subjects): 3 x 1012 vg kg-1.
In the cohort given the lowest dose, some FIX expression was observed. In the intermediate dose cohort, two out of three study subjects remain free of spontaneous hemorrhage without regular infusions of FIX, and one of these patients has had sustained expression levels of 20% for 12 months. In the highest dose cohort, both subjects have achieved expression levels above 40%, but they also experienced an immune response with variable neutralizing antibody titers to the AAV8 capsid. One study participant has returned to regular FIX infusions.
Previous research efforts to use gene therapy to deliver DNA carrying the genetic sequence encoding FIX have been frustrated by the immune response that these therapies provoke. The overall findings to date “underscore the difficulty of thinking that we can easily interrupt an immune response once the process has begun but, thankfully, there have been no inhibitors observed against FIX or against the variant used in this vector,” Dr. Monahan concluded.
An additional five patients will be included in this study.
The trial is sponsored by Baxalta. Dr. Monahan disclosed that he has consulted for and received research support from Baxalta.
On Twitter @dougbrunk
TORONTO – Researchers may be making some headway in the search for a gene therapy strategy to treat hemophilia B.
Preliminary findings from an ongoing phase 1-2 trial of an investigational gene therapy treatment in patients with hemophilia B were generally positive, based on results from the first seven patients.
Dr. Paul E. Monahan of the University of North Carolina Gene Therapy Center and Lineberger Comprehensive Cancer Center, Chapel Hill, reported that BAX 335 consists of a codon-optimized hyperactive FIX transgene driven by the liver-specific transthyretin (TTR) promoter in a nonintegrating adeno-associated viral (AAV) vector carrying a blood-clotting factor IX (FIX) gene.
The trial, the first in-human study of BAX 335, aims to evaluate the safety and kinetics of this gene therapy candidate. Dr. Monahan presented results from a combined follow-up of nearly 100 months on the first seven subjects, who were given one of three dosing schedules.
The adult male patients had hemophilia B and more than three hemorrhages per year requiring treatment with FIX, plasma FIX activity less than or equal to 2%, and a negative screen for hepatitis C. Patients with a family history of inhibitor to FIX protein or an allergic reaction to any FIX product were excluded, as were those with evidence of hepatic inflammation or cirrhosis.
The results for these seven subjects were generally positive. The BAX 335 doses were Cohort 1 (2 subjects): 1 x 1012 vg kg-1; Cohort 2 (3 subjects): 2 x 1012 vg kg-1; Cohort 3 (2 subjects): 3 x 1012 vg kg-1.
In the cohort given the lowest dose, some FIX expression was observed. In the intermediate dose cohort, two out of three study subjects remain free of spontaneous hemorrhage without regular infusions of FIX, and one of these patients has had sustained expression levels of 20% for 12 months. In the highest dose cohort, both subjects have achieved expression levels above 40%, but they also experienced an immune response with variable neutralizing antibody titers to the AAV8 capsid. One study participant has returned to regular FIX infusions.
Previous research efforts to use gene therapy to deliver DNA carrying the genetic sequence encoding FIX have been frustrated by the immune response that these therapies provoke. The overall findings to date “underscore the difficulty of thinking that we can easily interrupt an immune response once the process has begun but, thankfully, there have been no inhibitors observed against FIX or against the variant used in this vector,” Dr. Monahan concluded.
An additional five patients will be included in this study.
The trial is sponsored by Baxalta. Dr. Monahan disclosed that he has consulted for and received research support from Baxalta.
On Twitter @dougbrunk
TORONTO – Researchers may be making some headway in the search for a gene therapy strategy to treat hemophilia B.
Preliminary findings from an ongoing phase 1-2 trial of an investigational gene therapy treatment in patients with hemophilia B were generally positive, based on results from the first seven patients.
Dr. Paul E. Monahan of the University of North Carolina Gene Therapy Center and Lineberger Comprehensive Cancer Center, Chapel Hill, reported that BAX 335 consists of a codon-optimized hyperactive FIX transgene driven by the liver-specific transthyretin (TTR) promoter in a nonintegrating adeno-associated viral (AAV) vector carrying a blood-clotting factor IX (FIX) gene.
The trial, the first in-human study of BAX 335, aims to evaluate the safety and kinetics of this gene therapy candidate. Dr. Monahan presented results from a combined follow-up of nearly 100 months on the first seven subjects, who were given one of three dosing schedules.
The adult male patients had hemophilia B and more than three hemorrhages per year requiring treatment with FIX, plasma FIX activity less than or equal to 2%, and a negative screen for hepatitis C. Patients with a family history of inhibitor to FIX protein or an allergic reaction to any FIX product were excluded, as were those with evidence of hepatic inflammation or cirrhosis.
The results for these seven subjects were generally positive. The BAX 335 doses were Cohort 1 (2 subjects): 1 x 1012 vg kg-1; Cohort 2 (3 subjects): 2 x 1012 vg kg-1; Cohort 3 (2 subjects): 3 x 1012 vg kg-1.
In the cohort given the lowest dose, some FIX expression was observed. In the intermediate dose cohort, two out of three study subjects remain free of spontaneous hemorrhage without regular infusions of FIX, and one of these patients has had sustained expression levels of 20% for 12 months. In the highest dose cohort, both subjects have achieved expression levels above 40%, but they also experienced an immune response with variable neutralizing antibody titers to the AAV8 capsid. One study participant has returned to regular FIX infusions.
Previous research efforts to use gene therapy to deliver DNA carrying the genetic sequence encoding FIX have been frustrated by the immune response that these therapies provoke. The overall findings to date “underscore the difficulty of thinking that we can easily interrupt an immune response once the process has begun but, thankfully, there have been no inhibitors observed against FIX or against the variant used in this vector,” Dr. Monahan concluded.
An additional five patients will be included in this study.
The trial is sponsored by Baxalta. Dr. Monahan disclosed that he has consulted for and received research support from Baxalta.
On Twitter @dougbrunk
AT 2015 ISTH
Key clinical point: BAX 335, a new gene therapy candidate, is now in a phase I-II trial in hemophilia B patients.
Major finding: In the intermediate-dose cohort, two out of three study subjects remain free of spontaneous hemorrhage without regular infusions of FIX, and one of these patients has had sustained expression levels of 20% for 12 months.
Data source: Pilot study of seven adults.
Disclosures: The trial is sponsored by Baxalta. Dr. Monahan disclosed that he has consulted for and received research support from Baxalta.
Study establishes protocol for perioperative dabigatran discontinuation
TORONTO – In atrial fibrillation (AF) patients who must discontinue dabigatran for elective surgery, the risk of both stroke and major bleeding can be reduced to low levels using a formalized strategy for stopping and then restarting anticoagulation, according to results of a prospective study presented at the International Society on Thrombosis and Haemostasis Congress.
Among key findings presented at a press conference at the ISTH 2015 Congress, no strokes were recorded in more than 500 patients managed with the protocol, and the major bleeding rate was less than 2%, reported the study’s principal investigator, Dr. Sam Schulman, professor of hematology and thromboembolism, McMaster University, Hamilton, Ont.
Data from this study (Circulation 2015) were reported at the press conference alongside a second study of perioperative warfarin management. Both studies are potentially practice changing, because they supply evidence-based guidance for anticoagulation in patients with AF.
Based on the findings from these two studies, “it is important to get this message out” that there are now data available on which to base clinical decisions, reported Dr. Schulman, who is also president of the ISTH 2015 Congress. His data were presented alongside a study that found no benefit from heparin bridging in AF patients when warfarin was stopped 5 days in advance of surgery.
In the study presented by Dr. Schulman, 542 patients with AF who were on dabigatran and scheduled for elective surgery were managed on a prespecified protocol for risk assessment. The protocol provided a time for stopping dabigatran before surgery based on such factors as renal function and procedure-related bleeding risk. Dabigatran was restarted after surgery on prespecified measures of surgery complexity and severity of consequences if bleeding occurred.
The primary outcome evaluated in the study was major bleeding in the first 30 days. Other outcomes of interest included thromboembolic complications, death and minor bleeding.
Major bleeding was observed in 1.8% of patients, a rate that Dr. Schulman characterized as “low and acceptable” in the context of expected background bleeding rates. There were four deaths, but all were unrelated to either bleeding or arterial thromboembolism. The only thromboembolic complication was a single transient ischemic attack. Minor bleeding occurred in 5.2%.
On the basis of the protocol, about half of the patients discontinued dabigatran 24 hours before surgery. No patient discontinued therapy more than 96 hours prior to surgery. The median time to resumption of dabigatran after surgery was 1 day, but the point at which it was restarted ranged between hours and 2 days. Bridging, which describes the injection of heparin for short-term anticoagulation, was not employed preoperatively but was used in 1.7% of cases postoperatively.
At the press conference, data also were reported from the BRIDGE study. That study, published online in the New England Journal of Medicine (2015 June 22; epub ahead of print ), found that bridging was not an effective strategy in AF patients who discontinue warfarin prior to elective surgery. In the press conference, Dr. Thomas L. Ortel, hematology/oncology division, Duke University Medical Center, Durham, N.C., agreed with Dr. Schulman that this is an area where evidence is needed to guide care.
In the absence of data, “physicians do whatever they think is best,” Dr. Schulman noted at the press conference. Referring to strategies for stopping anticoagulants for surgery in patients with AF, Dr. Schulman said, “some of them stop the blood thinner too early because they are afraid that the patient is going to bleed during surgery and instead the patient can have a stroke. Some stop too late, and the patient can have bleeding.”
The data presented at the meeting provide an evidence base for clinical decisions. Dr. Schulman suggested that these data are meaningful for guiding care.
Dr. Ortel disclosed grant/research support from Eisai and Pfizer. Dr. Schulman had no disclosures.
TORONTO – In atrial fibrillation (AF) patients who must discontinue dabigatran for elective surgery, the risk of both stroke and major bleeding can be reduced to low levels using a formalized strategy for stopping and then restarting anticoagulation, according to results of a prospective study presented at the International Society on Thrombosis and Haemostasis Congress.
Among key findings presented at a press conference at the ISTH 2015 Congress, no strokes were recorded in more than 500 patients managed with the protocol, and the major bleeding rate was less than 2%, reported the study’s principal investigator, Dr. Sam Schulman, professor of hematology and thromboembolism, McMaster University, Hamilton, Ont.
Data from this study (Circulation 2015) were reported at the press conference alongside a second study of perioperative warfarin management. Both studies are potentially practice changing, because they supply evidence-based guidance for anticoagulation in patients with AF.
Based on the findings from these two studies, “it is important to get this message out” that there are now data available on which to base clinical decisions, reported Dr. Schulman, who is also president of the ISTH 2015 Congress. His data were presented alongside a study that found no benefit from heparin bridging in AF patients when warfarin was stopped 5 days in advance of surgery.
In the study presented by Dr. Schulman, 542 patients with AF who were on dabigatran and scheduled for elective surgery were managed on a prespecified protocol for risk assessment. The protocol provided a time for stopping dabigatran before surgery based on such factors as renal function and procedure-related bleeding risk. Dabigatran was restarted after surgery on prespecified measures of surgery complexity and severity of consequences if bleeding occurred.
The primary outcome evaluated in the study was major bleeding in the first 30 days. Other outcomes of interest included thromboembolic complications, death and minor bleeding.
Major bleeding was observed in 1.8% of patients, a rate that Dr. Schulman characterized as “low and acceptable” in the context of expected background bleeding rates. There were four deaths, but all were unrelated to either bleeding or arterial thromboembolism. The only thromboembolic complication was a single transient ischemic attack. Minor bleeding occurred in 5.2%.
On the basis of the protocol, about half of the patients discontinued dabigatran 24 hours before surgery. No patient discontinued therapy more than 96 hours prior to surgery. The median time to resumption of dabigatran after surgery was 1 day, but the point at which it was restarted ranged between hours and 2 days. Bridging, which describes the injection of heparin for short-term anticoagulation, was not employed preoperatively but was used in 1.7% of cases postoperatively.
At the press conference, data also were reported from the BRIDGE study. That study, published online in the New England Journal of Medicine (2015 June 22; epub ahead of print ), found that bridging was not an effective strategy in AF patients who discontinue warfarin prior to elective surgery. In the press conference, Dr. Thomas L. Ortel, hematology/oncology division, Duke University Medical Center, Durham, N.C., agreed with Dr. Schulman that this is an area where evidence is needed to guide care.
In the absence of data, “physicians do whatever they think is best,” Dr. Schulman noted at the press conference. Referring to strategies for stopping anticoagulants for surgery in patients with AF, Dr. Schulman said, “some of them stop the blood thinner too early because they are afraid that the patient is going to bleed during surgery and instead the patient can have a stroke. Some stop too late, and the patient can have bleeding.”
The data presented at the meeting provide an evidence base for clinical decisions. Dr. Schulman suggested that these data are meaningful for guiding care.
Dr. Ortel disclosed grant/research support from Eisai and Pfizer. Dr. Schulman had no disclosures.
TORONTO – In atrial fibrillation (AF) patients who must discontinue dabigatran for elective surgery, the risk of both stroke and major bleeding can be reduced to low levels using a formalized strategy for stopping and then restarting anticoagulation, according to results of a prospective study presented at the International Society on Thrombosis and Haemostasis Congress.
Among key findings presented at a press conference at the ISTH 2015 Congress, no strokes were recorded in more than 500 patients managed with the protocol, and the major bleeding rate was less than 2%, reported the study’s principal investigator, Dr. Sam Schulman, professor of hematology and thromboembolism, McMaster University, Hamilton, Ont.
Data from this study (Circulation 2015) were reported at the press conference alongside a second study of perioperative warfarin management. Both studies are potentially practice changing, because they supply evidence-based guidance for anticoagulation in patients with AF.
Based on the findings from these two studies, “it is important to get this message out” that there are now data available on which to base clinical decisions, reported Dr. Schulman, who is also president of the ISTH 2015 Congress. His data were presented alongside a study that found no benefit from heparin bridging in AF patients when warfarin was stopped 5 days in advance of surgery.
In the study presented by Dr. Schulman, 542 patients with AF who were on dabigatran and scheduled for elective surgery were managed on a prespecified protocol for risk assessment. The protocol provided a time for stopping dabigatran before surgery based on such factors as renal function and procedure-related bleeding risk. Dabigatran was restarted after surgery on prespecified measures of surgery complexity and severity of consequences if bleeding occurred.
The primary outcome evaluated in the study was major bleeding in the first 30 days. Other outcomes of interest included thromboembolic complications, death and minor bleeding.
Major bleeding was observed in 1.8% of patients, a rate that Dr. Schulman characterized as “low and acceptable” in the context of expected background bleeding rates. There were four deaths, but all were unrelated to either bleeding or arterial thromboembolism. The only thromboembolic complication was a single transient ischemic attack. Minor bleeding occurred in 5.2%.
On the basis of the protocol, about half of the patients discontinued dabigatran 24 hours before surgery. No patient discontinued therapy more than 96 hours prior to surgery. The median time to resumption of dabigatran after surgery was 1 day, but the point at which it was restarted ranged between hours and 2 days. Bridging, which describes the injection of heparin for short-term anticoagulation, was not employed preoperatively but was used in 1.7% of cases postoperatively.
At the press conference, data also were reported from the BRIDGE study. That study, published online in the New England Journal of Medicine (2015 June 22; epub ahead of print ), found that bridging was not an effective strategy in AF patients who discontinue warfarin prior to elective surgery. In the press conference, Dr. Thomas L. Ortel, hematology/oncology division, Duke University Medical Center, Durham, N.C., agreed with Dr. Schulman that this is an area where evidence is needed to guide care.
In the absence of data, “physicians do whatever they think is best,” Dr. Schulman noted at the press conference. Referring to strategies for stopping anticoagulants for surgery in patients with AF, Dr. Schulman said, “some of them stop the blood thinner too early because they are afraid that the patient is going to bleed during surgery and instead the patient can have a stroke. Some stop too late, and the patient can have bleeding.”
The data presented at the meeting provide an evidence base for clinical decisions. Dr. Schulman suggested that these data are meaningful for guiding care.
Dr. Ortel disclosed grant/research support from Eisai and Pfizer. Dr. Schulman had no disclosures.
AT 2015 ISTH CONGRESS
Key clinical point: The risk of stroke and major bleeding can be reduced to low levels using a formalized strategy for stopping and then restarting dabigatran.
Major finding: The protocol developed provided a time for stopping dabigatran before surgery based on such factors as renal function and procedure-related bleeding risk. Dabigatran was restarted after surgery on prespecified measures of surgery complexity and severity of consequences if bleeding occurred.
Data source: 542 patients with AF who were on dabigatran and scheduled for elective surgery were managed on a prespecified protocol for risk assessment.
Disclosures: Dr. Ortel disclosed grant/research support from Eisai and Pfizer. Dr. Schulman had no disclosures.
Idarucizumab reverses dabigatran’s anticoagulant effects
TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.
Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).
“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.
In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.
Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.
“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.
Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.
“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”
In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”
“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.
Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.
Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.
“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.
“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.
Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.
Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.
TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.
Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).
“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.
In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.
Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.
“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.
Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.
“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”
In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”
“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.
Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.
Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.
“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.
“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.
Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.
Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.
TORONTO – Idarucizumab is a promising agent that quickly and safely reverses the anticoagulant effects of dabigatran whether the goal is to control serious bleeding or to permit urgent surgery, according to interim results of a multicenter trial.
Idarucizumab is a monoclonal antibody that binds to dabigatran to reverse its activity. The data, presented by Dr. V. Charles Pollack Jr. at the International Society on Thrombosis and Haemostasis congress, involved the first 90 patients of an ongoing trial with a planned enrollment of 300. The data from this trial, called REVERSE-AD, were published online simultaneously with the June 22 presentation at the congress (N. Engl. J. Med 2015 [doi:10.1056/NEJMoa1502000]).
“Non–vitamin K antagonist oral anticoagulants (NOACs) are generally safer than warfarin, and provide similar or improved efficacy in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of venous thromboembolism,” Dr. Pollack said in an interview. “Nonetheless, serious bleeding events may occur with NOAC use, and patients taking one of these agents occasionally require urgent surgery or other intervention for which normal hemostasis is required,” added Dr. Pollack, chair of the department of emergency medicine at Pennsylvania Hospital in Philadelphia.
In RE-VERSE AD (a study of the reversal effects of idarucizumab on active dabigatran), the first 90 patients were divided into two distinct groups. Group A, with 51 patients, included those on dabigatran with serious bleeding. Group B, with 39 patients, required reversal of dabigatran for urgent or emergent procedures. In both, idarucizumab provided a median maximum reversal of 100% (95% confidence interval, 100-100) of the anticoagulation effect within 4 hours.
Clotting assays were normalized almost immediately in almost 90% of patients, and the effect was durable, with 80% having measured dabigatran levels reflecting no significant anticoagulation 24 hours later, Dr. Pollack said.
“Clinical outcomes were quite good in this multimorbid patient population, with restoration of hemostasis as reported by local investigators achieved in less than 12 hours when assessable, and with 92% of surgical patients being reported as having normal hemostasis at the time of the procedure,” he said.
Idarucizumab was generally well tolerated in the patient population. “There were no serious adverse events related to the reversal agent ... and only one patient experienced a thrombotic complication within 72 hours, and that patient had not been restarted on any antithrombotic medications,” Dr. Pollack said.
“The study is ongoing,” he added, “but these interim results show rather convincingly that idarucizumab completely and safely reverses the anticoagulant effects of dabigatran within minutes.”
In addition, Dr. Pollack said the availability of a specific reversal agent for dabigatran would enhance its safety margin, and thus alleviate the fears of providers who may hesitate to use a NOAC because of the lack of an “antidote.”
“In fact, most such cases can already be successfully and safely managed with general support and ‘tincture of time’ (the half-life of dabigatran is much shorter than that of warfarin), but having a specific ‘go-to’ option could streamline the care of the most significantly compromised patients,” he said.
Dr. Pollack emphasized, however, that idarucizumab is a specific reversal agent for dabigatran, not an antidote. “To me, the latter would imply that idarucizumab immediately stops bleeding associated with active use of dabigatran,” he said.
Providers should realize that while idarucizumab seems capable of removing dabigatran-induced coagulopathy from the list of concerns when managing a patient with serious bleeding or before a “sharp” procedure, bleeding is a multifaceted issue that also may be due to traumatized blood vessels, other causes of coagulopathy such as liver disease, or concurrent use of antiplatelet medications, he said.
“The patient with a serious or life-threatening bleed on dabigatran will likely need additional care to investigate and manage such concerns,” Dr. Pollack said. “But at least idarucizumab can specifically, safely, and rapidly address the primary consideration.
“The safety of anticoagulation therapy with dabigatran is further enhanced with idarucizumab, a specific reversal agent that won’t need to be used often, but the availability of which would be reassuring to prescribers,” he concluded.
Boehringer Ingelheim sponsored RE-VERSE AD. Idarucizumab was given a fast-track status by the Food and Drug Administration, and BI submitted a new drug application in March 2015, according to the company.
Dr. Pollack reported receiving personal fees from BI, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.
AT 2015 ISTH CONGRESS
Key clinical point: The investigational monoclonal antibody idarucizumab reversed the anticoagulant effects of dabigatran.
Major finding: Idarucizumab provided a median maximum dabigatran reversal of 100% (95% CI, 100-100) of the anticoagulation effect within 4 hours in an interim analysis.
Data source: RE-VERSE AD, a prospective cohort study in which 90 patients treated with dabigatran who had uncontrolled bleeding or required emergency surgery or procedures were given 5.0 g idarucizumab.
Disclosures: Boehringer Ingelheim sponsored RE-VERSE AD. Dr. Pollack reported receiving personal fees from Boehringer Ingelheim, Janssen, Daiichi-Sankyo, Bristol-Myers Squibb, and Pfizer. Disclosures for all the investigators are available at NEJM.org.
Promacta approved for pediatric treatment of chronic ITP
The Food and Drug Administration has approved Promacta for the treatment of chronic immune thrombocytopenia in children 6 years and older, Novartis, the drug’s manufacturer, announced in a statement.
Promacta (eltrombopag) is an oral thrombopoietin receptor agonist that increases platelet production by inducing stimulation and differentiation of megakaryocytes from bone marrow stem cells. Chronic immune thrombocytopenia (ITP) patients often have low platelet counts and are at risk for significant bleeding.
Promacta was approved for adult use in 2008; the drug was evaluated for pediatric use in PETIT and PETIT2, two multiphase, double-blind placebo-controlled trials designed to evaluate the drug’s safety profile. Both studies found Promacta’s safety to be consistent with the known safety profile of Promacta in chronic ITP in adults.
Promacta’s manufacturers say the drug can be useful for chronic ITP patients who have had an insufficient response to the most commonly available and used therapies for chronic ITP, such as corticosteroids, intravenous immunoglobulin, or splenectomy. ITP affects as many as 5 in 100,000 children each year.
The most common adverse reactions to Promacta in pediatric chronic ITP patients were upper respiratory tract infection, nasopharyngitis, and rhinitis. In adults, Promacta has been associated with nausea, diarrhea, upper respiratory tract infection, and vomiting; rarer but more serious side effects include liver problems, high platelet counts, a higher risk for blood clots, and new or worsened cataracts.
The Food and Drug Administration has approved Promacta for the treatment of chronic immune thrombocytopenia in children 6 years and older, Novartis, the drug’s manufacturer, announced in a statement.
Promacta (eltrombopag) is an oral thrombopoietin receptor agonist that increases platelet production by inducing stimulation and differentiation of megakaryocytes from bone marrow stem cells. Chronic immune thrombocytopenia (ITP) patients often have low platelet counts and are at risk for significant bleeding.
Promacta was approved for adult use in 2008; the drug was evaluated for pediatric use in PETIT and PETIT2, two multiphase, double-blind placebo-controlled trials designed to evaluate the drug’s safety profile. Both studies found Promacta’s safety to be consistent with the known safety profile of Promacta in chronic ITP in adults.
Promacta’s manufacturers say the drug can be useful for chronic ITP patients who have had an insufficient response to the most commonly available and used therapies for chronic ITP, such as corticosteroids, intravenous immunoglobulin, or splenectomy. ITP affects as many as 5 in 100,000 children each year.
The most common adverse reactions to Promacta in pediatric chronic ITP patients were upper respiratory tract infection, nasopharyngitis, and rhinitis. In adults, Promacta has been associated with nausea, diarrhea, upper respiratory tract infection, and vomiting; rarer but more serious side effects include liver problems, high platelet counts, a higher risk for blood clots, and new or worsened cataracts.
The Food and Drug Administration has approved Promacta for the treatment of chronic immune thrombocytopenia in children 6 years and older, Novartis, the drug’s manufacturer, announced in a statement.
Promacta (eltrombopag) is an oral thrombopoietin receptor agonist that increases platelet production by inducing stimulation and differentiation of megakaryocytes from bone marrow stem cells. Chronic immune thrombocytopenia (ITP) patients often have low platelet counts and are at risk for significant bleeding.
Promacta was approved for adult use in 2008; the drug was evaluated for pediatric use in PETIT and PETIT2, two multiphase, double-blind placebo-controlled trials designed to evaluate the drug’s safety profile. Both studies found Promacta’s safety to be consistent with the known safety profile of Promacta in chronic ITP in adults.
Promacta’s manufacturers say the drug can be useful for chronic ITP patients who have had an insufficient response to the most commonly available and used therapies for chronic ITP, such as corticosteroids, intravenous immunoglobulin, or splenectomy. ITP affects as many as 5 in 100,000 children each year.
The most common adverse reactions to Promacta in pediatric chronic ITP patients were upper respiratory tract infection, nasopharyngitis, and rhinitis. In adults, Promacta has been associated with nausea, diarrhea, upper respiratory tract infection, and vomiting; rarer but more serious side effects include liver problems, high platelet counts, a higher risk for blood clots, and new or worsened cataracts.
DDW: VIDEO: What we don’t know in the management of liver disease and coagulopathy
WASHINGTON – Your patient has cirrhosis, platelets 60,000 mm3, an INR of 2.0, serum creatinine of 1.2 mg/dL, and requires an endoscopic retrograde cholangiopancreatography with sphincterotomy.
What do you do next?
Management of a patient such as this is challenging, but not just because of the long-perceived risk for bleeding, Dr. Patrick S. Kamath of the Mayo Clinic in Rochester, Minn., said during a clinical symposium at the annual Digestive Disease Week.
Several other factors must be considered, including the clotting risk in patients with liver disease and the fact that procedure-related bleeding risk cannot be adequately determined preprocedure. Transfusions also carry their own dangers in this patient population and should be approached with caution, he said.
To hear more from this world-renowned liver expert, check out our interview as we sat down with Dr. Kamath at this year’s DDW.
Dr. Kamath reported no relevant financial conflicts.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
WASHINGTON – Your patient has cirrhosis, platelets 60,000 mm3, an INR of 2.0, serum creatinine of 1.2 mg/dL, and requires an endoscopic retrograde cholangiopancreatography with sphincterotomy.
What do you do next?
Management of a patient such as this is challenging, but not just because of the long-perceived risk for bleeding, Dr. Patrick S. Kamath of the Mayo Clinic in Rochester, Minn., said during a clinical symposium at the annual Digestive Disease Week.
Several other factors must be considered, including the clotting risk in patients with liver disease and the fact that procedure-related bleeding risk cannot be adequately determined preprocedure. Transfusions also carry their own dangers in this patient population and should be approached with caution, he said.
To hear more from this world-renowned liver expert, check out our interview as we sat down with Dr. Kamath at this year’s DDW.
Dr. Kamath reported no relevant financial conflicts.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
WASHINGTON – Your patient has cirrhosis, platelets 60,000 mm3, an INR of 2.0, serum creatinine of 1.2 mg/dL, and requires an endoscopic retrograde cholangiopancreatography with sphincterotomy.
What do you do next?
Management of a patient such as this is challenging, but not just because of the long-perceived risk for bleeding, Dr. Patrick S. Kamath of the Mayo Clinic in Rochester, Minn., said during a clinical symposium at the annual Digestive Disease Week.
Several other factors must be considered, including the clotting risk in patients with liver disease and the fact that procedure-related bleeding risk cannot be adequately determined preprocedure. Transfusions also carry their own dangers in this patient population and should be approached with caution, he said.
To hear more from this world-renowned liver expert, check out our interview as we sat down with Dr. Kamath at this year’s DDW.
Dr. Kamath reported no relevant financial conflicts.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @pwendl
AT DDW 2015
FDA approves new formulation of deferasirox for iron chelation
The Food and Drug Administration approved a new formulation of deferasirox as a once-daily oral tablet for iron chelation, Novartis announced.
The product, to be marketed as Jadenu, is indicated for chronic iron overload due to blood transfusions in patients 2 years of age and older, and chronic iron overload in non–transfusion-dependent thalassemia in patients 10 years of age or older. Novartis said it is the only once-daily oral iron chelator that can be swallowed whole, with or without food.
Jadenu is a reformulation of Exjade, a dispersible tablet that must be mixed in liquid and taken on an empty stomach.
The new product received its green light under the FDA’s accelerated approval process based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, Novartis said.
Nausea, vomiting, diarrhea, stomach pain, increases in kidney laboratory values, and skin rash were the most common side effects reported in deferasirox clinical trials. Novartis warned that the drug may cause serious kidney problems, liver problems, and bleeding in the stomach or intestines, and in some cases, death from these complications. The company added that it is not known if Jadenu is safe or effective when taken with other iron chelation therapy, and controlled clinical trials of deferasirox for patients with myelodysplastic syndromes and chronic iron overload due to blood transfusions have not been performed.
Full prescribing information is available at http://tinyurl.com/nspjlek.
The Food and Drug Administration approved a new formulation of deferasirox as a once-daily oral tablet for iron chelation, Novartis announced.
The product, to be marketed as Jadenu, is indicated for chronic iron overload due to blood transfusions in patients 2 years of age and older, and chronic iron overload in non–transfusion-dependent thalassemia in patients 10 years of age or older. Novartis said it is the only once-daily oral iron chelator that can be swallowed whole, with or without food.
Jadenu is a reformulation of Exjade, a dispersible tablet that must be mixed in liquid and taken on an empty stomach.
The new product received its green light under the FDA’s accelerated approval process based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, Novartis said.
Nausea, vomiting, diarrhea, stomach pain, increases in kidney laboratory values, and skin rash were the most common side effects reported in deferasirox clinical trials. Novartis warned that the drug may cause serious kidney problems, liver problems, and bleeding in the stomach or intestines, and in some cases, death from these complications. The company added that it is not known if Jadenu is safe or effective when taken with other iron chelation therapy, and controlled clinical trials of deferasirox for patients with myelodysplastic syndromes and chronic iron overload due to blood transfusions have not been performed.
Full prescribing information is available at http://tinyurl.com/nspjlek.
The Food and Drug Administration approved a new formulation of deferasirox as a once-daily oral tablet for iron chelation, Novartis announced.
The product, to be marketed as Jadenu, is indicated for chronic iron overload due to blood transfusions in patients 2 years of age and older, and chronic iron overload in non–transfusion-dependent thalassemia in patients 10 years of age or older. Novartis said it is the only once-daily oral iron chelator that can be swallowed whole, with or without food.
Jadenu is a reformulation of Exjade, a dispersible tablet that must be mixed in liquid and taken on an empty stomach.
The new product received its green light under the FDA’s accelerated approval process based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, Novartis said.
Nausea, vomiting, diarrhea, stomach pain, increases in kidney laboratory values, and skin rash were the most common side effects reported in deferasirox clinical trials. Novartis warned that the drug may cause serious kidney problems, liver problems, and bleeding in the stomach or intestines, and in some cases, death from these complications. The company added that it is not known if Jadenu is safe or effective when taken with other iron chelation therapy, and controlled clinical trials of deferasirox for patients with myelodysplastic syndromes and chronic iron overload due to blood transfusions have not been performed.
Full prescribing information is available at http://tinyurl.com/nspjlek.
Lentiviral gene therapy could prove useful for adults with hemophilia
Liver-directed lentiviral gene therapy is an effective treatment for hemophilia B in dogs, according to Alessio Cantore, Ph.D., and his associates.
The investigators found that all of the dogs administered the treatment were still alive 5 years after the therapy. Spontaneous bleeding was cut down significantly from before the therapy began. No significant side effects were seen in any of the dogs, and no lentiviral vector DNA was found in blood samples, proving long-term effectiveness of vector-transduced cells.
“If we extrapolate the observed dose response in dogs to humans, the current lentiviral vector–manufacturing capacity could support the treatment of adult patients with hemophilia” if a hyperfunctional IX transgene factor were used, Dr. Cantore and his associates wrote. “Lentiviral vectors may complement other available vectors to address some of the outstanding challenges posed by liver gene therapy for the treatment of hemophilia and conceivably other diseases.”
Read the full study in Science Translational Medicine (doi: 10.1126/scitranslmed.aaa1405).
Liver-directed lentiviral gene therapy is an effective treatment for hemophilia B in dogs, according to Alessio Cantore, Ph.D., and his associates.
The investigators found that all of the dogs administered the treatment were still alive 5 years after the therapy. Spontaneous bleeding was cut down significantly from before the therapy began. No significant side effects were seen in any of the dogs, and no lentiviral vector DNA was found in blood samples, proving long-term effectiveness of vector-transduced cells.
“If we extrapolate the observed dose response in dogs to humans, the current lentiviral vector–manufacturing capacity could support the treatment of adult patients with hemophilia” if a hyperfunctional IX transgene factor were used, Dr. Cantore and his associates wrote. “Lentiviral vectors may complement other available vectors to address some of the outstanding challenges posed by liver gene therapy for the treatment of hemophilia and conceivably other diseases.”
Read the full study in Science Translational Medicine (doi: 10.1126/scitranslmed.aaa1405).
Liver-directed lentiviral gene therapy is an effective treatment for hemophilia B in dogs, according to Alessio Cantore, Ph.D., and his associates.
The investigators found that all of the dogs administered the treatment were still alive 5 years after the therapy. Spontaneous bleeding was cut down significantly from before the therapy began. No significant side effects were seen in any of the dogs, and no lentiviral vector DNA was found in blood samples, proving long-term effectiveness of vector-transduced cells.
“If we extrapolate the observed dose response in dogs to humans, the current lentiviral vector–manufacturing capacity could support the treatment of adult patients with hemophilia” if a hyperfunctional IX transgene factor were used, Dr. Cantore and his associates wrote. “Lentiviral vectors may complement other available vectors to address some of the outstanding challenges posed by liver gene therapy for the treatment of hemophilia and conceivably other diseases.”
Read the full study in Science Translational Medicine (doi: 10.1126/scitranslmed.aaa1405).
JAK inhibitor more effective than standard therapy for polycythemia vera
Treatment with ruxolitinib, an oral inhibitor of Janus kinase 1 and 2, was associated with significantly better responses and improvement in symptoms in patients with polycythemia vera who had not responded to or had experienced unacceptable side effects with hydroxyurea, compared with those who received standard therapy, in a phase III, open-label study, Dr. Alessandro Vannucchi of the University of Florence (Italy) and his associates reported.
In the RESPONSE study, patients with splenomegaly who required phlebotomy for control of hematocrit and had an inadequate response or had experienced unacceptable side effects with hydroxyurea were randomized to treatment with the kinase inhibitor (110 patients) or to interferon and other standard treatments (112). After 32 weeks, 21% of those treated with ruxolitinib had met the primary endpoint, which was control of hematocrit and at least a 35% reduction in spleen volume (measured by MRI or CT), compared with 1% of those on standard treatment, a statistically significant difference with a P value less than .001. A significantly greater proportion of those in the ruxolitinib-treated group also met the two individual components of the primary endpoint.
“Response rates with ruxolitinib were similar among patients who had unacceptable side effects from hydroxyurea and those who had an inadequate response to hydroxyurea. ... and there was no relationship between response and age, sex, or baseline spleen volume,” the authors wrote. The study is the basis of the recent Food and Drug Administration approval of ruxolitinib for this indication (N. Engl. J. Med. 2015 Jan. 28. [doi:10.1056/NEJMoa1409002])Other endpoints included complete hematologic remission, achieved by 24% of those treated with ruxolitinib vs. 9% on standard therapy. At week 32, almost half of those on ruxolitinib had at least a 50% reduction in the total symptom score that assessed disease-related symptoms vs. 5% of those on standard therapy.
Some hematologic adverse events were more common among those on ruxolitinib: 2% developed grade 3 or 4 anemia, and 5% developed grade 3 or 4 thrombocytopenia, compared with 0% and 4% of those on standard treatment. In addition, 6% of those on ruxolitinib developed herpes zoster infections, compared with none of those on standard therapy. One patient on ruxolitinib and six patients on standard therapy had thromboembolic events. Three patients treated with ruxolitinib developed myelofibrosis 120-469 days after being randomized to treatment (about 5-9 years after they had been diagnosed with polycythemia vera) and one patient was diagnosed with acute myeloid leukemia after 56 days of treatment. Among those on standard therapy, one patient developed myelofibrosis after 101 days of treatment and two were diagnosed with myelofibrosis more than 300 days after they crossed over to treatment with ruxolitinib, including one patient who progressed to acute myelogenous leukemia.
While many patients with polycythemia vera respond adequately to hydroxyurea, the most commonly used cytoreductive agent used to treat polycythemia vera, about 25% do not have a satisfactory response or experience unacceptable side effects, “and alternative treatment options are needed for these patients,” the authors said.
The mean age of the patients in the study was 60-62 years, and they had been diagnosed with polycythemia vera a median of 8-9 years previously; 60% of those in the ruxolitinib group and 71% in the standard therapy group were men. The investigators chose the standard therapy, which included hydroxyurea at a dose that did not result in unacceptable side effects (59%), interferon (12%), anagrelide (7%), immunomodulators (4.5%), and pipobroman (2%); and in about 15% of patients, no medication was given.
Ruxolitinib was approved by the Food and Drug Administration in December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. It was initially approved by the FDA in 2011, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post essential thrombocythemia myelofibrosis.
Ruxolitinib inhibits Janus kinase (JAK) 1 and JAK2, which “mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function,” according to the prescribing information. It is marketed as Jakafi by Incyte.
Most of the patients on ruxolitinib are continuing treatment in the RESPONSE study, which is ongoing but is not recruiting any more patients, according to the authors.
The study was sponsored by Incyte and Novartis, which has licensed ruxolitinib from Incyte for development and commercialization outside the United States. Dr. Vannucchi disclosed having received grant support and serving as an adviser for Novartis; three authors are employees of Incyte; three are employees of Novartis in the United States or Switzerland, six authors had no disclosures, and one author received grants from Incyte during the study. The remaining three authors reported serving on the advisory board, serving as speakers or lecturers, and/or receiving grant support from Novartis.
Treatment with ruxolitinib, an oral inhibitor of Janus kinase 1 and 2, was associated with significantly better responses and improvement in symptoms in patients with polycythemia vera who had not responded to or had experienced unacceptable side effects with hydroxyurea, compared with those who received standard therapy, in a phase III, open-label study, Dr. Alessandro Vannucchi of the University of Florence (Italy) and his associates reported.
In the RESPONSE study, patients with splenomegaly who required phlebotomy for control of hematocrit and had an inadequate response or had experienced unacceptable side effects with hydroxyurea were randomized to treatment with the kinase inhibitor (110 patients) or to interferon and other standard treatments (112). After 32 weeks, 21% of those treated with ruxolitinib had met the primary endpoint, which was control of hematocrit and at least a 35% reduction in spleen volume (measured by MRI or CT), compared with 1% of those on standard treatment, a statistically significant difference with a P value less than .001. A significantly greater proportion of those in the ruxolitinib-treated group also met the two individual components of the primary endpoint.
“Response rates with ruxolitinib were similar among patients who had unacceptable side effects from hydroxyurea and those who had an inadequate response to hydroxyurea. ... and there was no relationship between response and age, sex, or baseline spleen volume,” the authors wrote. The study is the basis of the recent Food and Drug Administration approval of ruxolitinib for this indication (N. Engl. J. Med. 2015 Jan. 28. [doi:10.1056/NEJMoa1409002])Other endpoints included complete hematologic remission, achieved by 24% of those treated with ruxolitinib vs. 9% on standard therapy. At week 32, almost half of those on ruxolitinib had at least a 50% reduction in the total symptom score that assessed disease-related symptoms vs. 5% of those on standard therapy.
Some hematologic adverse events were more common among those on ruxolitinib: 2% developed grade 3 or 4 anemia, and 5% developed grade 3 or 4 thrombocytopenia, compared with 0% and 4% of those on standard treatment. In addition, 6% of those on ruxolitinib developed herpes zoster infections, compared with none of those on standard therapy. One patient on ruxolitinib and six patients on standard therapy had thromboembolic events. Three patients treated with ruxolitinib developed myelofibrosis 120-469 days after being randomized to treatment (about 5-9 years after they had been diagnosed with polycythemia vera) and one patient was diagnosed with acute myeloid leukemia after 56 days of treatment. Among those on standard therapy, one patient developed myelofibrosis after 101 days of treatment and two were diagnosed with myelofibrosis more than 300 days after they crossed over to treatment with ruxolitinib, including one patient who progressed to acute myelogenous leukemia.
While many patients with polycythemia vera respond adequately to hydroxyurea, the most commonly used cytoreductive agent used to treat polycythemia vera, about 25% do not have a satisfactory response or experience unacceptable side effects, “and alternative treatment options are needed for these patients,” the authors said.
The mean age of the patients in the study was 60-62 years, and they had been diagnosed with polycythemia vera a median of 8-9 years previously; 60% of those in the ruxolitinib group and 71% in the standard therapy group were men. The investigators chose the standard therapy, which included hydroxyurea at a dose that did not result in unacceptable side effects (59%), interferon (12%), anagrelide (7%), immunomodulators (4.5%), and pipobroman (2%); and in about 15% of patients, no medication was given.
Ruxolitinib was approved by the Food and Drug Administration in December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. It was initially approved by the FDA in 2011, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post essential thrombocythemia myelofibrosis.
Ruxolitinib inhibits Janus kinase (JAK) 1 and JAK2, which “mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function,” according to the prescribing information. It is marketed as Jakafi by Incyte.
Most of the patients on ruxolitinib are continuing treatment in the RESPONSE study, which is ongoing but is not recruiting any more patients, according to the authors.
The study was sponsored by Incyte and Novartis, which has licensed ruxolitinib from Incyte for development and commercialization outside the United States. Dr. Vannucchi disclosed having received grant support and serving as an adviser for Novartis; three authors are employees of Incyte; three are employees of Novartis in the United States or Switzerland, six authors had no disclosures, and one author received grants from Incyte during the study. The remaining three authors reported serving on the advisory board, serving as speakers or lecturers, and/or receiving grant support from Novartis.
Treatment with ruxolitinib, an oral inhibitor of Janus kinase 1 and 2, was associated with significantly better responses and improvement in symptoms in patients with polycythemia vera who had not responded to or had experienced unacceptable side effects with hydroxyurea, compared with those who received standard therapy, in a phase III, open-label study, Dr. Alessandro Vannucchi of the University of Florence (Italy) and his associates reported.
In the RESPONSE study, patients with splenomegaly who required phlebotomy for control of hematocrit and had an inadequate response or had experienced unacceptable side effects with hydroxyurea were randomized to treatment with the kinase inhibitor (110 patients) or to interferon and other standard treatments (112). After 32 weeks, 21% of those treated with ruxolitinib had met the primary endpoint, which was control of hematocrit and at least a 35% reduction in spleen volume (measured by MRI or CT), compared with 1% of those on standard treatment, a statistically significant difference with a P value less than .001. A significantly greater proportion of those in the ruxolitinib-treated group also met the two individual components of the primary endpoint.
“Response rates with ruxolitinib were similar among patients who had unacceptable side effects from hydroxyurea and those who had an inadequate response to hydroxyurea. ... and there was no relationship between response and age, sex, or baseline spleen volume,” the authors wrote. The study is the basis of the recent Food and Drug Administration approval of ruxolitinib for this indication (N. Engl. J. Med. 2015 Jan. 28. [doi:10.1056/NEJMoa1409002])Other endpoints included complete hematologic remission, achieved by 24% of those treated with ruxolitinib vs. 9% on standard therapy. At week 32, almost half of those on ruxolitinib had at least a 50% reduction in the total symptom score that assessed disease-related symptoms vs. 5% of those on standard therapy.
Some hematologic adverse events were more common among those on ruxolitinib: 2% developed grade 3 or 4 anemia, and 5% developed grade 3 or 4 thrombocytopenia, compared with 0% and 4% of those on standard treatment. In addition, 6% of those on ruxolitinib developed herpes zoster infections, compared with none of those on standard therapy. One patient on ruxolitinib and six patients on standard therapy had thromboembolic events. Three patients treated with ruxolitinib developed myelofibrosis 120-469 days after being randomized to treatment (about 5-9 years after they had been diagnosed with polycythemia vera) and one patient was diagnosed with acute myeloid leukemia after 56 days of treatment. Among those on standard therapy, one patient developed myelofibrosis after 101 days of treatment and two were diagnosed with myelofibrosis more than 300 days after they crossed over to treatment with ruxolitinib, including one patient who progressed to acute myelogenous leukemia.
While many patients with polycythemia vera respond adequately to hydroxyurea, the most commonly used cytoreductive agent used to treat polycythemia vera, about 25% do not have a satisfactory response or experience unacceptable side effects, “and alternative treatment options are needed for these patients,” the authors said.
The mean age of the patients in the study was 60-62 years, and they had been diagnosed with polycythemia vera a median of 8-9 years previously; 60% of those in the ruxolitinib group and 71% in the standard therapy group were men. The investigators chose the standard therapy, which included hydroxyurea at a dose that did not result in unacceptable side effects (59%), interferon (12%), anagrelide (7%), immunomodulators (4.5%), and pipobroman (2%); and in about 15% of patients, no medication was given.
Ruxolitinib was approved by the Food and Drug Administration in December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. It was initially approved by the FDA in 2011, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post essential thrombocythemia myelofibrosis.
Ruxolitinib inhibits Janus kinase (JAK) 1 and JAK2, which “mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function,” according to the prescribing information. It is marketed as Jakafi by Incyte.
Most of the patients on ruxolitinib are continuing treatment in the RESPONSE study, which is ongoing but is not recruiting any more patients, according to the authors.
The study was sponsored by Incyte and Novartis, which has licensed ruxolitinib from Incyte for development and commercialization outside the United States. Dr. Vannucchi disclosed having received grant support and serving as an adviser for Novartis; three authors are employees of Incyte; three are employees of Novartis in the United States or Switzerland, six authors had no disclosures, and one author received grants from Incyte during the study. The remaining three authors reported serving on the advisory board, serving as speakers or lecturers, and/or receiving grant support from Novartis.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Ruxolitinib, now approved for treatment of polycythemia vera in the United States, is an alternative to hydroxyurea in patients who have failed treatment with or cannot tolerate hydroxyurea.
Major finding: After 8 months, treatment with ruxolitinib resulted in significantly better responses than standard therapy in patients with polycythemia vera who had an unsatisfactory response or unacceptable side effects with hydroxyurea, as measured by control of hematocrit and at least a 35% reduction in spleen volume (21% vs. 1%).
Data source: A phase III, international, open-label, randomized trial of 222 patients with polycythemia vera who had unacceptable side effects or did not respond adequately to hydroxyurea or standard therapy.
Disclosures: The study was sponsored by Incyte and Novartis. Four authors reported serving on the advisory board, serving as speakers or lecturers, and/or receiving grant support from Novartis; one author received grants from Incyte during the study; six are employees of Incyte or Novartis; and six authors had no disclosures.
FDA expands ruxolitinib approval to include polycythemia vera
Ruxolitinib has been approved for the treatment of polycythemia vera in patients who have an inadequate response to hydroxyurea or are unable to tolerate that drug.
The Food and Drug Administration approved the drug, a Janus-associated kinase (JAK) inhibitor marketed as Jakafi, on Dec. 4. Ruxolitinib received a priority, expedited review at the agency.
“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.
Ruxolitinib “represents an important advance for patients with uncontrolled PV,” said Dr. Srdan Verstovsek, a professor in the leukemia department at the University of Texas MD Anderson Cancer Center, Houston, in a statement issued by ruxolitinib maker Incyte Corp. “For the first time, we are able to provide these patients a treatment that has been shown to provide effective and consistent control of their blood counts and reduce spleen volume.”
Polycythemia vera, a chronic disease, causes a hyperproliferation of red blood cells. Patients may also experience an increase in white blood cells and platelets, and splenomegaly, and are at higher risk for heart attack and stroke.
“The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease,” said Dr. Pazdur.
Ruxolitinib was first approved in 2011 for myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.
The new indication is for polycythemia vera patients who do not respond to or cannot tolerate hydroxyurea.
The drug’s safety and effectiveness were evaluated in a study of 222 patients who received either ruxolitinib or the best available therapy, and who had the disease for at least 24 weeks, had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure and exhibited an enlarged spleen.
Of patients receiving ruxolitinib, 21% experienced a reduction in the need for a phlebotomy and a reduction in spleen volume by the end of the 32-week study, compared with 1% of participants who received best available therapy.
The most common side effects were anemia and thrombocytopenia, dizziness, constipation, and shingles.
On Twitter @aliciaault
Ruxolitinib has been approved for the treatment of polycythemia vera in patients who have an inadequate response to hydroxyurea or are unable to tolerate that drug.
The Food and Drug Administration approved the drug, a Janus-associated kinase (JAK) inhibitor marketed as Jakafi, on Dec. 4. Ruxolitinib received a priority, expedited review at the agency.
“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.
Ruxolitinib “represents an important advance for patients with uncontrolled PV,” said Dr. Srdan Verstovsek, a professor in the leukemia department at the University of Texas MD Anderson Cancer Center, Houston, in a statement issued by ruxolitinib maker Incyte Corp. “For the first time, we are able to provide these patients a treatment that has been shown to provide effective and consistent control of their blood counts and reduce spleen volume.”
Polycythemia vera, a chronic disease, causes a hyperproliferation of red blood cells. Patients may also experience an increase in white blood cells and platelets, and splenomegaly, and are at higher risk for heart attack and stroke.
“The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease,” said Dr. Pazdur.
Ruxolitinib was first approved in 2011 for myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.
The new indication is for polycythemia vera patients who do not respond to or cannot tolerate hydroxyurea.
The drug’s safety and effectiveness were evaluated in a study of 222 patients who received either ruxolitinib or the best available therapy, and who had the disease for at least 24 weeks, had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure and exhibited an enlarged spleen.
Of patients receiving ruxolitinib, 21% experienced a reduction in the need for a phlebotomy and a reduction in spleen volume by the end of the 32-week study, compared with 1% of participants who received best available therapy.
The most common side effects were anemia and thrombocytopenia, dizziness, constipation, and shingles.
On Twitter @aliciaault
Ruxolitinib has been approved for the treatment of polycythemia vera in patients who have an inadequate response to hydroxyurea or are unable to tolerate that drug.
The Food and Drug Administration approved the drug, a Janus-associated kinase (JAK) inhibitor marketed as Jakafi, on Dec. 4. Ruxolitinib received a priority, expedited review at the agency.
“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.
Ruxolitinib “represents an important advance for patients with uncontrolled PV,” said Dr. Srdan Verstovsek, a professor in the leukemia department at the University of Texas MD Anderson Cancer Center, Houston, in a statement issued by ruxolitinib maker Incyte Corp. “For the first time, we are able to provide these patients a treatment that has been shown to provide effective and consistent control of their blood counts and reduce spleen volume.”
Polycythemia vera, a chronic disease, causes a hyperproliferation of red blood cells. Patients may also experience an increase in white blood cells and platelets, and splenomegaly, and are at higher risk for heart attack and stroke.
“The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease,” said Dr. Pazdur.
Ruxolitinib was first approved in 2011 for myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.
The new indication is for polycythemia vera patients who do not respond to or cannot tolerate hydroxyurea.
The drug’s safety and effectiveness were evaluated in a study of 222 patients who received either ruxolitinib or the best available therapy, and who had the disease for at least 24 weeks, had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure and exhibited an enlarged spleen.
Of patients receiving ruxolitinib, 21% experienced a reduction in the need for a phlebotomy and a reduction in spleen volume by the end of the 32-week study, compared with 1% of participants who received best available therapy.
The most common side effects were anemia and thrombocytopenia, dizziness, constipation, and shingles.
On Twitter @aliciaault
Management of Bleeding Complications in Patients with Cancer
Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.
To read the full article in PDF:
Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.
To read the full article in PDF:
Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.
To read the full article in PDF: