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Anti-CD38 antibodies poised to transform myeloma treatment
SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.
The ORR in newly diagnosed patients was 100%, including partial responses and very good partial responses, and 50% in the relapsed group, including one complete response, study coauthor Dr. María-Victoria Mateos said at the briefing.
Daratumumab does not appear to have a negative effect on stem cell mobilization, with five patients electively taken off study for autologous stem cell transplantation after cycle 4.
Three of the seven patients in the POM-D arm dropped out (one because of physician decision and two because of disease progression).
The addition of daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity, said Dr. Mateos of University Hospital of Salamanca, Spain.
Adverse events possibly or probably related to daratumumab included one grade 3 neutropenia in the VD arm, one grade 3 thrombocytopenia in the VMP arm, and one serious infectious pneumonia in the POM-D arm. There were a few infusion-related reactions, but most were grade 1 or 2 and occurred within the first infusions, she said.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” Dr. Philippe Moreau, lead study author, of University Hospital of Nantes, France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
Dr. Brad S. Kahl, press briefing moderator, of the University of Wisconsin-Madison, was enthusiastic about the potential for anti-CD38 antibodies to transform the treatment of multiple myeloma.
“Obviously it’s very, very early, probably too early to plant a victory flag in the ground,” he said. “Having said that, the early data is very promising and totally justifies all the comments about bringing these drugs forward, aggressively moving them into the front line.”
Phase III studies are ongoing or will be initiated shortly with daratumumab plus VD in relapsed myeloma (MMY3004-CASTOR), with VMP in non–transplant eligible patients (MMY3007-ALCYONE), and with VTD as induction therapy (MMY3006/IFM-HOVON-CASSIOPEIA).
SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.
The ORR in newly diagnosed patients was 100%, including partial responses and very good partial responses, and 50% in the relapsed group, including one complete response, study coauthor Dr. María-Victoria Mateos said at the briefing.
Daratumumab does not appear to have a negative effect on stem cell mobilization, with five patients electively taken off study for autologous stem cell transplantation after cycle 4.
Three of the seven patients in the POM-D arm dropped out (one because of physician decision and two because of disease progression).
The addition of daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity, said Dr. Mateos of University Hospital of Salamanca, Spain.
Adverse events possibly or probably related to daratumumab included one grade 3 neutropenia in the VD arm, one grade 3 thrombocytopenia in the VMP arm, and one serious infectious pneumonia in the POM-D arm. There were a few infusion-related reactions, but most were grade 1 or 2 and occurred within the first infusions, she said.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” Dr. Philippe Moreau, lead study author, of University Hospital of Nantes, France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
Dr. Brad S. Kahl, press briefing moderator, of the University of Wisconsin-Madison, was enthusiastic about the potential for anti-CD38 antibodies to transform the treatment of multiple myeloma.
“Obviously it’s very, very early, probably too early to plant a victory flag in the ground,” he said. “Having said that, the early data is very promising and totally justifies all the comments about bringing these drugs forward, aggressively moving them into the front line.”
Phase III studies are ongoing or will be initiated shortly with daratumumab plus VD in relapsed myeloma (MMY3004-CASTOR), with VMP in non–transplant eligible patients (MMY3007-ALCYONE), and with VTD as induction therapy (MMY3006/IFM-HOVON-CASSIOPEIA).
SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.
The ORR in newly diagnosed patients was 100%, including partial responses and very good partial responses, and 50% in the relapsed group, including one complete response, study coauthor Dr. María-Victoria Mateos said at the briefing.
Daratumumab does not appear to have a negative effect on stem cell mobilization, with five patients electively taken off study for autologous stem cell transplantation after cycle 4.
Three of the seven patients in the POM-D arm dropped out (one because of physician decision and two because of disease progression).
The addition of daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity, said Dr. Mateos of University Hospital of Salamanca, Spain.
Adverse events possibly or probably related to daratumumab included one grade 3 neutropenia in the VD arm, one grade 3 thrombocytopenia in the VMP arm, and one serious infectious pneumonia in the POM-D arm. There were a few infusion-related reactions, but most were grade 1 or 2 and occurred within the first infusions, she said.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” Dr. Philippe Moreau, lead study author, of University Hospital of Nantes, France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
Dr. Brad S. Kahl, press briefing moderator, of the University of Wisconsin-Madison, was enthusiastic about the potential for anti-CD38 antibodies to transform the treatment of multiple myeloma.
“Obviously it’s very, very early, probably too early to plant a victory flag in the ground,” he said. “Having said that, the early data is very promising and totally justifies all the comments about bringing these drugs forward, aggressively moving them into the front line.”
Phase III studies are ongoing or will be initiated shortly with daratumumab plus VD in relapsed myeloma (MMY3004-CASTOR), with VMP in non–transplant eligible patients (MMY3007-ALCYONE), and with VTD as induction therapy (MMY3006/IFM-HOVON-CASSIOPEIA).
AT ASH 2014
Key clinical point: The investigational anti-CD38 antibodies SAR650984 and daratumumab in combination with standard regimens were highly active in untreated and relapsed/refractory multiple myeloma.
Major finding: Overall response rates were 58% in patients treated with SAR650984, and 100% and 50%, respectively, in newly diagnosed and relapsed patients given daratumumab.
Data source: Two phase Ib studies in patients with newly diagnosed or relapsed/refractory multiple myeloma.
Disclosures: Sanofi Oncology sponsored the SAR650984 study. Dr. Martin reported research funding from Sanofi and serving as a speaker for Novartis. Genmab sponsored the daratumumab study. Dr. Mateos and Dr. Moreau reported ties with Janssen. Dr. Kahl reported ties with numerous drug companies.
VTE risk models target a formidable surgery foe
CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.
“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.
The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.
Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.
Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.
“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.
She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.
• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.
VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.
“So, while it was simple, it only works well for the high-risk category,” she said.
• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.
Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.
• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.
The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.
• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m2, male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.
Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.
• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).
Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.
“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.
For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.
A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).
Dr. Kibbe reported having no financial disclosures.
CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.
“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.
The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.
Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.
Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.
“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.
She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.
• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.
VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.
“So, while it was simple, it only works well for the high-risk category,” she said.
• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.
Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.
• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.
The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.
• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m2, male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.
Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.
• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).
Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.
“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.
For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.
A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).
Dr. Kibbe reported having no financial disclosures.
CHICAGO – Implementation of preoperative venous thromboembolism prophylaxis requires a highly individualized approach and a little boost from information technology, one expert suggested.
“What may not be appreciated by some vascular surgeons is that for certain procedures we do, our patients actually have a high VTE [venous thromboembolism] risk. I know people think, ‘We use heparin, so our patients aren’t at high risk,’ but they actually are,” Dr. Melina Kibbe said at a symposium on vascular surgery sponsored by Northwestern University.
The VTE risk is 4.2% for open thoracoabdominal aortic aneurysm repair and 2.2% for thoracic endovascular aortic repair in the American College of Surgeons National Surgical Quality Improvement Program database. That may be an underestimation, however, because the NSQIP database captures only symptomatic events documented by imaging and those events occurring in the first 30 days after surgery.
Smaller studies looking at the problem prospectively suggest the VTE risk is closer to 2%-12% after open aortic surgery and 5.3% after endovascular aortic repair, she said.
Add to that the U.S. Surgeon General’s 2008 call to action to prevent VTE and the Institute of Medicine’s stance that failure to provide VTE prophylaxis qualifies as a medical error, and it would be tempting for vascular surgeons to prescribe pharmacologic prophylaxis for all of their patients, or at least do so based on the type of procedure.
“But VTE formation is really secondary to patient-specific and procedure-related factors,” said Dr. Kibbe, a professor of vascular surgery at Northwestern University in Chicago.
She highlighted five current VTE risk assessment models (RAMs) and the potential returns when RAMs are incorporated into clinical decision support systems.
• Kucher model. One of the earlier and most straightforward RAMs is the Kucher model. It assessed eight weighted risk factors (advanced age, obesity, bed rest, hormone replacement therapy/oral contraceptives, major surgery, cancer, prior VTE, and hypercoagulability) and provided surgeons with electronic alerts regarding prophylaxis.
VTE rates dropped from 8.2% to 4.9% in the high-risk category (score ≥ 4) with the use of the simple physician reminders (N. Engl. J. Med. 2005;352:969-77). Prospective validation showed that VTE increased proportionally with higher scores, Dr. Kibbe said. On the other hand, the model lacked sensitivity at low VTE risk, because 20% of patients with a score of 4 or less actually had VTEs.
“So, while it was simple, it only works well for the high-risk category,” she said.
• Rogers model. One of the most vigorously studied and developed RAMs is the Rogers model (J. Am. Coll. Surg. 2007;204:1211-21). It identified 15 variables (including lab values, patient characteristics, disease states, work relative-value unit, and type of operation) that were independently associated with VTE formation among 183,609 patients undergoing general, vascular, or thoracic procedures at 142 Veterans Health Administration and private hospitals. Each variable is assigned a value from 0 to 9 and added together to create a Rogers score.
Validation showed that VTE risk correlates with the Rogers score, rising from 0.11% for patients with a low score (< 7) to 1.32% for those with a high score (> 10), Dr. Kibbe said. Criticisms of the model are that it is complex, VTE incidence in the entire cohort was low at just 0.63%, the type of VTE prophylaxis used was unclear, and the model lacks prospective validation in a vascular surgery cohort.
• Caprini model. The most commonly used RAM is the 2005 Caprini model (Dis. Mon. 2005;51:70-8), which assigns a weighted score based on more than 30 VTE risk factors compiled by the authors. It has been prospectively validated in numerous studies and shown to accurately stratify 30-day VTE risk at 0.5% for patients at very low risk, 1.5% for low risk, 3% for moderate risk, and 6% for high risk.
The Caprini model, however, was not developed with the same rigor as the Rogers RAM, some of the risk factors have been shown not to be a risk for VTE, and it is complex, Dr. Kibbe observed.
• Pannucci model. The Pannucci model was created specifically to counteract the complexity of the Rogers and Caprini RAMs and incorporates only seven risk factors (personal history of VTE, current cancer, age ≥ 60 years, body mass index ≥ 40 kg/m2, male sex, sepsis/septic shock/systemic inflammatory response syndrome, and family history of VTE) into a weighted index for 90-day VTE risk (Chest 2014;145:567-73). The model was developed using a statewide database and a derivation cohort made up of 20% vascular surgery patients.
Both the derivation and validation cohorts identified an 18-fold variation in VTE risk from the lowest- to highest-risk surgical population, showing that the model stratifies patients correctly. Further prospective validation is needed, Dr. Kibbe said.
• Scarborough model. Finally, in an attempt to develop a RAM specific to vascular surgery patients, Dr. John Scarborough and colleagues examined 6,035 patients undergoing open AAA repair in the NSQIP database. The 30-day VTE rate was 2.4% for the entire cohort. Eight independent perioperative risk factors were identified and used to create a nonweighted scoring system (J. Am. Coll. Surg. 2012;214:620-6).
Overall, 65% of patients had 0-1 risk factor and a VTE incidence of 1.5%, while 15% had 3 or more risk factors and a VTE incidence of 6.1%. The Scarborough model has good risk stratification, Dr. Kibbe said, but it is limited by the aforementioned criticisms regarding the NSQIP database, and it also needs prospective validation.
“We all know that proper VTE prophylaxis is very important for our patients; but we need mechanisms by which the attention given to this need for prophylaxis, which is a lot, is turned into proper implementation,” she said.
For Dr. Kibbe and her colleagues, proper implementation meant developing a RAM that was incorporated into the electronic medical record system for all surgical patients at the Jesse Brown VA Medical Center in Chicago. Clinicians were prompted to complete the RAM upon placing orders for preanesthesia testing clearance, and the clinical decision support system would provide a recommended prophylaxis regimen and easily selected electronic orders that could be signed.
A pre- and postimplementation analysis involving 400 consecutive patients revealed an 82% increase in patients with preoperative VTE prophylaxis ordered (22% vs. 40%), a 75% decrease in inappropriate cancellation of orders more than 12 hours before surgery (37% vs. 9%), and a nearly sevenfold increase in the number of patients receiving pharmacologic and mechanical prophylaxis (5% vs. 32%), she said. There was an 80% and 36% decline in DVT rates at 30 and 90 days postoperative, but event rates were too low to detect a significant difference (J. Vasc. Surg. 2010;51:648-54).
Dr. Kibbe reported having no financial disclosures.
AT THE NORTHWESTERN VASCULAR SYMPOSIUM
CAR-T cell therapy rolls on in pediatric ALL
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
AT ASH 2014
Key clinical point: CAR-T cell therapy continues to provide durable responses in early studies of children with refractory ALL.
Major finding: Complete remission occurred in 36 of 39 patients (92%) treated with CAR-T cell therapy.
Data source: Phase I/IIa a study in 39 children and young adults with relapsed, refractory acute lymphoblastic leukemia.
Disclosures: The authors reported financial ties with Novartis, the study sponsor.
VALOR: Baby step forward or misstep in AML?
SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.
The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.
More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).
The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.
Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.
Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”
“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.
He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.
Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.
“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.
VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.
In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.
When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.
There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).
In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).
“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”
During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”
Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.
Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.
Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.
Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.
The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.
More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).
The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.
Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.
Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”
“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.
He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.
Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.
“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.
VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.
In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.
When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.
There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).
In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).
“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”
During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”
Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.
Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.
Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.
Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.
The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.
More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).
The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.
Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.
Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”
“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.
He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.
Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.
“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.
VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.
In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.
When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.
There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).
In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).
“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”
During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”
Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.
Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.
Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.
Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
AT ASH 2014
Key clinical point: Vosaroxin plus cytarabine failed to significantly improve overall survival in relapsed or refractory AML, but may offer older patients a new option.
Major finding: Median overall survival was 7.5 months for vosaroxin plus cytarabine vs. 6.1 months for cytarabine alone (HR, 0.865; P = .06).
Data source: Randomized, phase III trial in 711 patients with first relapsed or refractory acute myeloid leukemia.
Disclosures: Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
Nursing home-onset C. difficile infections cut wide swath
PHILADELPHIA – Clostridium difficile infections among nursing home residents resulted in some 31,000 hospitalizations and 9,000 deaths nationally in 2012, population-based surveillance data suggest.
“Nursing home-onset CDI is associated with substantial morbidity and mortality,” Dr. Fernanda Lessa reported at an annual scientific meeting on infectious diseases.
Nursing home residents are at higher risk of C. difficile infections (CDI) because of advanced age, frequent healthcare utilization, extended lengths of stay, and exposure to antimicrobials. The national burden of CDI in this setting, however, is not well characterized, said Dr. Lessa of the Centers for Disease Control and Prevention, Atlanta.
The investigators, lead by the CDC’s Dr. Jennifer C. Hunter analyzed surveillance data from 10 states in the Emerging Infections Program (EIP), representing a population of 11.4 million Americans and encompassing 382 nursing homes in 2012. A regression model was used to calculate incidence controlling for identified predictors of high nursing home-onset CDI incidence that vary by region. Sampling weights were used to estimate the national burden of infections and numbers of hospitalizations, recurrences, and deaths.
Nursing home-onset CDI cases were defined as a C. difficile-positive stool sample by toxin or molecular assay during 2012 in a surveillance area resident at least one year of age without a positive test in the prior 8 weeks and a positive stool sample collected in a nursing home resident or within 3 days after hospital admission from a nursing home.
A total of 16,565 CDI cases were identified, of which 3,513 (21%) were nursing home-onset CDI, she said.
A full medical record review of 272 random nursing home-onset CDI cases revealed that most patients received antibiotics in the 12 weeks before testing positive (77%) and had onset of the disease within a month after hospital discharge (76%), Dr. Lessa observed.
Approximately 13% required hospitalization within 7 days of testing positive, 2% required ICU admission, 20% had recurrent disease within 2-8 weeks, and 8% died within 30 days of a positive specimen.
After adjusting for age and diagnostic testing methods, an estimated 115,811 cases of nursing home-onset CDI occurred in 2012, with the highest rate among those aged 65-84 years (58,857 cases; rate 157.97/100,000 population).
Of these, an estimated 31,644 patients required hospitalization, 21,103 experienced recurrence, and 9,053 died within 30 days, Dr. Lessa reported.
“Strategies to reduce unnecessary antibiotic use in both acute and long-term care settings may lead to decreases in CDI onset in nursing homes in the U.S.,” she suggested.
During a discussion of the results, it was noted that the data are very consistent with multiple other studies showing that CDI in long-term care facilities is occurring within 30 days of transfer to the hospital, raising the question of whether the major problem isn’t antibiotic stewardship in the hospital setting.
Dr. Lessa pointed out that 30% of cases were not hospitalized in the 12 weeks prior to CDI onset, but went on to say, “I think we should focus on both [settings], but I completely agree that antimicrobial stewardship in the acute care setting will likely have a major impact in reducing nursing home C. difficile rates.”
ID Week is a joint meeting of the Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases Society.
PHILADELPHIA – Clostridium difficile infections among nursing home residents resulted in some 31,000 hospitalizations and 9,000 deaths nationally in 2012, population-based surveillance data suggest.
“Nursing home-onset CDI is associated with substantial morbidity and mortality,” Dr. Fernanda Lessa reported at an annual scientific meeting on infectious diseases.
Nursing home residents are at higher risk of C. difficile infections (CDI) because of advanced age, frequent healthcare utilization, extended lengths of stay, and exposure to antimicrobials. The national burden of CDI in this setting, however, is not well characterized, said Dr. Lessa of the Centers for Disease Control and Prevention, Atlanta.
The investigators, lead by the CDC’s Dr. Jennifer C. Hunter analyzed surveillance data from 10 states in the Emerging Infections Program (EIP), representing a population of 11.4 million Americans and encompassing 382 nursing homes in 2012. A regression model was used to calculate incidence controlling for identified predictors of high nursing home-onset CDI incidence that vary by region. Sampling weights were used to estimate the national burden of infections and numbers of hospitalizations, recurrences, and deaths.
Nursing home-onset CDI cases were defined as a C. difficile-positive stool sample by toxin or molecular assay during 2012 in a surveillance area resident at least one year of age without a positive test in the prior 8 weeks and a positive stool sample collected in a nursing home resident or within 3 days after hospital admission from a nursing home.
A total of 16,565 CDI cases were identified, of which 3,513 (21%) were nursing home-onset CDI, she said.
A full medical record review of 272 random nursing home-onset CDI cases revealed that most patients received antibiotics in the 12 weeks before testing positive (77%) and had onset of the disease within a month after hospital discharge (76%), Dr. Lessa observed.
Approximately 13% required hospitalization within 7 days of testing positive, 2% required ICU admission, 20% had recurrent disease within 2-8 weeks, and 8% died within 30 days of a positive specimen.
After adjusting for age and diagnostic testing methods, an estimated 115,811 cases of nursing home-onset CDI occurred in 2012, with the highest rate among those aged 65-84 years (58,857 cases; rate 157.97/100,000 population).
Of these, an estimated 31,644 patients required hospitalization, 21,103 experienced recurrence, and 9,053 died within 30 days, Dr. Lessa reported.
“Strategies to reduce unnecessary antibiotic use in both acute and long-term care settings may lead to decreases in CDI onset in nursing homes in the U.S.,” she suggested.
During a discussion of the results, it was noted that the data are very consistent with multiple other studies showing that CDI in long-term care facilities is occurring within 30 days of transfer to the hospital, raising the question of whether the major problem isn’t antibiotic stewardship in the hospital setting.
Dr. Lessa pointed out that 30% of cases were not hospitalized in the 12 weeks prior to CDI onset, but went on to say, “I think we should focus on both [settings], but I completely agree that antimicrobial stewardship in the acute care setting will likely have a major impact in reducing nursing home C. difficile rates.”
ID Week is a joint meeting of the Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases Society.
PHILADELPHIA – Clostridium difficile infections among nursing home residents resulted in some 31,000 hospitalizations and 9,000 deaths nationally in 2012, population-based surveillance data suggest.
“Nursing home-onset CDI is associated with substantial morbidity and mortality,” Dr. Fernanda Lessa reported at an annual scientific meeting on infectious diseases.
Nursing home residents are at higher risk of C. difficile infections (CDI) because of advanced age, frequent healthcare utilization, extended lengths of stay, and exposure to antimicrobials. The national burden of CDI in this setting, however, is not well characterized, said Dr. Lessa of the Centers for Disease Control and Prevention, Atlanta.
The investigators, lead by the CDC’s Dr. Jennifer C. Hunter analyzed surveillance data from 10 states in the Emerging Infections Program (EIP), representing a population of 11.4 million Americans and encompassing 382 nursing homes in 2012. A regression model was used to calculate incidence controlling for identified predictors of high nursing home-onset CDI incidence that vary by region. Sampling weights were used to estimate the national burden of infections and numbers of hospitalizations, recurrences, and deaths.
Nursing home-onset CDI cases were defined as a C. difficile-positive stool sample by toxin or molecular assay during 2012 in a surveillance area resident at least one year of age without a positive test in the prior 8 weeks and a positive stool sample collected in a nursing home resident or within 3 days after hospital admission from a nursing home.
A total of 16,565 CDI cases were identified, of which 3,513 (21%) were nursing home-onset CDI, she said.
A full medical record review of 272 random nursing home-onset CDI cases revealed that most patients received antibiotics in the 12 weeks before testing positive (77%) and had onset of the disease within a month after hospital discharge (76%), Dr. Lessa observed.
Approximately 13% required hospitalization within 7 days of testing positive, 2% required ICU admission, 20% had recurrent disease within 2-8 weeks, and 8% died within 30 days of a positive specimen.
After adjusting for age and diagnostic testing methods, an estimated 115,811 cases of nursing home-onset CDI occurred in 2012, with the highest rate among those aged 65-84 years (58,857 cases; rate 157.97/100,000 population).
Of these, an estimated 31,644 patients required hospitalization, 21,103 experienced recurrence, and 9,053 died within 30 days, Dr. Lessa reported.
“Strategies to reduce unnecessary antibiotic use in both acute and long-term care settings may lead to decreases in CDI onset in nursing homes in the U.S.,” she suggested.
During a discussion of the results, it was noted that the data are very consistent with multiple other studies showing that CDI in long-term care facilities is occurring within 30 days of transfer to the hospital, raising the question of whether the major problem isn’t antibiotic stewardship in the hospital setting.
Dr. Lessa pointed out that 30% of cases were not hospitalized in the 12 weeks prior to CDI onset, but went on to say, “I think we should focus on both [settings], but I completely agree that antimicrobial stewardship in the acute care setting will likely have a major impact in reducing nursing home C. difficile rates.”
ID Week is a joint meeting of the Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases Society.
AT ID WEEK 2014
Key clinical point: Nursing home-onset C. difficile infections are associated with significant morbidity and mortality.
Major finding: An estimated 115,811 cases of nursing home-onset C. difficile occurred in 2012 nationally.
Data source: Population-based surveillance data from 10 states and 382 nursing homes.
Disclosures: Dr. Lessa reported having no financial disclosures.
ICD lead extraction complication rates warrant surgical backup
CHICAGO– Transvenous lead extraction was associated with a significant risk of urgent cardiac surgery and mortality in a real-world cohort of patients undergoing procedures across a wide spectrum of centers and operators.
Among the 11,304 extractions, the major complication rate was 2.3% and mortality rate 0.9%.
While the complication rate was in line with previously published single-center registry data, the mortality rate was more than twice that reported in recent single-center studies from high-volume centers (0.9% vs. 0.4%), Dr. Nitesh Sood reported at the American Heart Association annual scientific sessions.
Of the 98 perioperative deaths, 18 occurred during the lead extraction procedure.
Another 41 patients (16%) required urgent cardiac surgery, of whom 14 (34%) died during or in the immediate postoperative period after surgery.
“Thus, while overall rate of major complications remains low, there exists a significant risk of urgent cardiac surgery and mortality during transvenous lead extractions [TLE] performed in the ‘real world.’ Appropriate training of all personnel involved and optimal cardiothoracic surgical back-up at centers performing TLE is imperative,” Dr. Sood of the Southcoast Health System, Fall River, Mass., concluded.
The analysis is the largest real-world cohort of TLE involving 11,304 patients with an implantable cardioverter defibrillator (ICD) in the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) ICD Registry with lead extraction data submitted between April 2010 and July 2012. Major complication was a combined endpoint of major operative complications, postoperative or in-hospital mortality, as defined by the NCDR ICD Registry.
The 258 complications included 62 cardiac arrests, 55 pericardial tamponades, 47 pneumothoraces, and 40 cardiac perforations.
In multivariate analysis, significant predictors of any complication were female sex (adjusted odds ratio, 1.46), heart failure admission vs. lead extraction admission (OR, 2.6), noncardiac admission vs. lead extraction admission (OR, 2.4), lead-only procedure vs. extraction during generator change/upgrade (OR, 1.76), age of lead (OR, 1.08), and clinical status requiring lead replacement (OR, 2.2). Dr. Sood reported.
Among lead characteristics, multivariate predictors of major perioperative complications included at least three concurrent leads extracted (OR, 2.13), longer implant duration (OR, 1.13), flat coil design vs. round (OR, 2.68), greater proximal coil surface area (OR, 1.04), and dislodgement of other leads during extraction (OR, 3.97), he noted.
CHICAGO– Transvenous lead extraction was associated with a significant risk of urgent cardiac surgery and mortality in a real-world cohort of patients undergoing procedures across a wide spectrum of centers and operators.
Among the 11,304 extractions, the major complication rate was 2.3% and mortality rate 0.9%.
While the complication rate was in line with previously published single-center registry data, the mortality rate was more than twice that reported in recent single-center studies from high-volume centers (0.9% vs. 0.4%), Dr. Nitesh Sood reported at the American Heart Association annual scientific sessions.
Of the 98 perioperative deaths, 18 occurred during the lead extraction procedure.
Another 41 patients (16%) required urgent cardiac surgery, of whom 14 (34%) died during or in the immediate postoperative period after surgery.
“Thus, while overall rate of major complications remains low, there exists a significant risk of urgent cardiac surgery and mortality during transvenous lead extractions [TLE] performed in the ‘real world.’ Appropriate training of all personnel involved and optimal cardiothoracic surgical back-up at centers performing TLE is imperative,” Dr. Sood of the Southcoast Health System, Fall River, Mass., concluded.
The analysis is the largest real-world cohort of TLE involving 11,304 patients with an implantable cardioverter defibrillator (ICD) in the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) ICD Registry with lead extraction data submitted between April 2010 and July 2012. Major complication was a combined endpoint of major operative complications, postoperative or in-hospital mortality, as defined by the NCDR ICD Registry.
The 258 complications included 62 cardiac arrests, 55 pericardial tamponades, 47 pneumothoraces, and 40 cardiac perforations.
In multivariate analysis, significant predictors of any complication were female sex (adjusted odds ratio, 1.46), heart failure admission vs. lead extraction admission (OR, 2.6), noncardiac admission vs. lead extraction admission (OR, 2.4), lead-only procedure vs. extraction during generator change/upgrade (OR, 1.76), age of lead (OR, 1.08), and clinical status requiring lead replacement (OR, 2.2). Dr. Sood reported.
Among lead characteristics, multivariate predictors of major perioperative complications included at least three concurrent leads extracted (OR, 2.13), longer implant duration (OR, 1.13), flat coil design vs. round (OR, 2.68), greater proximal coil surface area (OR, 1.04), and dislodgement of other leads during extraction (OR, 3.97), he noted.
CHICAGO– Transvenous lead extraction was associated with a significant risk of urgent cardiac surgery and mortality in a real-world cohort of patients undergoing procedures across a wide spectrum of centers and operators.
Among the 11,304 extractions, the major complication rate was 2.3% and mortality rate 0.9%.
While the complication rate was in line with previously published single-center registry data, the mortality rate was more than twice that reported in recent single-center studies from high-volume centers (0.9% vs. 0.4%), Dr. Nitesh Sood reported at the American Heart Association annual scientific sessions.
Of the 98 perioperative deaths, 18 occurred during the lead extraction procedure.
Another 41 patients (16%) required urgent cardiac surgery, of whom 14 (34%) died during or in the immediate postoperative period after surgery.
“Thus, while overall rate of major complications remains low, there exists a significant risk of urgent cardiac surgery and mortality during transvenous lead extractions [TLE] performed in the ‘real world.’ Appropriate training of all personnel involved and optimal cardiothoracic surgical back-up at centers performing TLE is imperative,” Dr. Sood of the Southcoast Health System, Fall River, Mass., concluded.
The analysis is the largest real-world cohort of TLE involving 11,304 patients with an implantable cardioverter defibrillator (ICD) in the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) ICD Registry with lead extraction data submitted between April 2010 and July 2012. Major complication was a combined endpoint of major operative complications, postoperative or in-hospital mortality, as defined by the NCDR ICD Registry.
The 258 complications included 62 cardiac arrests, 55 pericardial tamponades, 47 pneumothoraces, and 40 cardiac perforations.
In multivariate analysis, significant predictors of any complication were female sex (adjusted odds ratio, 1.46), heart failure admission vs. lead extraction admission (OR, 2.6), noncardiac admission vs. lead extraction admission (OR, 2.4), lead-only procedure vs. extraction during generator change/upgrade (OR, 1.76), age of lead (OR, 1.08), and clinical status requiring lead replacement (OR, 2.2). Dr. Sood reported.
Among lead characteristics, multivariate predictors of major perioperative complications included at least three concurrent leads extracted (OR, 2.13), longer implant duration (OR, 1.13), flat coil design vs. round (OR, 2.68), greater proximal coil surface area (OR, 1.04), and dislodgement of other leads during extraction (OR, 3.97), he noted.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Appropriate training and optimal cardiothoracic surgical backup is necessary at all centers performing lead extractions, because of a significant risk of urgent cardiac surgery and death.
Major finding: The major complication rate was 2.3% and mortality rate 0.9%.
Data source: Retrospective analysis of 11,304 patients with transvenous lead extraction in the NCDR ICD Registry.
Disclosures: The study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Sood reported having no financial disclosures. Three coauthors reported relationships with device makers.
CABG plus mitral repair put under spotlight
CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.
At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).
Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m2 from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.
At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).
On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).
“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.
The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.
The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).
The mean LVESVI at baseline was 54.8 mL/m2 in the CABG-alone group and 59.6 mL/m2 in the combined procedure group.
At 12 months, mean LVESVIs were 46.1 mL/m2 and 49.6 mL/m2, respectively.
The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.
Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.
“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.
In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.
What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.
“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.
Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).
The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.
The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.
At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).
Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m2 from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.
At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).
On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).
“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.
The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.
The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).
The mean LVESVI at baseline was 54.8 mL/m2 in the CABG-alone group and 59.6 mL/m2 in the combined procedure group.
At 12 months, mean LVESVIs were 46.1 mL/m2 and 49.6 mL/m2, respectively.
The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.
Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.
“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.
In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.
What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.
“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.
Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).
The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.
The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.
At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).
Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m2 from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.
At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).
On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).
“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.
The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.
The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).
The mean LVESVI at baseline was 54.8 mL/m2 in the CABG-alone group and 59.6 mL/m2 in the combined procedure group.
At 12 months, mean LVESVIs were 46.1 mL/m2 and 49.6 mL/m2, respectively.
The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.
Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.
“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.
In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.
What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.
“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.
Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).
The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.
The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
AT THE AHA SCIENTIFIC SESSIONS 2014
Key clinical point: CABG plus mitral repair did not significantly improve left ventricular remodeling at 1 year, and was associated with some untoward events.
Major finding: At 12 months, mean LVESVI was 46.1 mL/m2 with CABG alone and 49.6 mL/m2 with CABG plus mitral repair.
Data source: A randomized trial in 301 patients with moderate mitral regurgitation.
Disclosures: The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
Mechanical mitral valves outshine bioprostheses in long term
CHICAGO – Biologic prostheses in patients with severe ischemic mitral regurgitation undergoing mitral valve replacement were associated with worse valve hemodynamics and decreased functional capacity, compared with mechanical prostheses, long-term follow-up data showed.
Dr. Carlo Fino reported the results of a retrospective study involving 86 consecutive patients who received mitral valve replacement with either biologic (41) or mechanical (45) prostheses for chronic ischemic mitral valve regurgitation. Their mean age was 63 years and 60 were male.
Significantly more patients with mechanical bioprostheses had a history of heart failure (53% vs. 27%), but all other baseline demographic, clinical, and echocardiographic data were similar. Patients with atrial fibrillation were excluded from the study.
Operative variables were also similar between the mechanical and biologic groups including cardiopulmonary bypass time (mean, 85 vs. 82 minutes), aortic cross clamp time (mean, 71 vs. 68 minutes), arterial grafts per patient (1.2 for both groups), anastomoses per patient (2.7 vs. 2.4), and use of intra-aortic balloon pump (2 patients vs. 1 patient).
At 32 months’ follow-up, patients with mechanical versus biologic prostheses had significantly higher left ventricular ejection fraction (49% vs. 42%) and cardiac index (4.8 vs. 4.5 L/min per square meter) during exercise, Dr. Fino reported at the American Heart Association scientific sessions.
Systolic pulmonary arterial pressure increased modestly during exercise with a mechanical valve, but was significantly higher with a biologic valve (41 vs. 59 mm Hg), as was mitral peak gradient (11.26 vs. 16 mm Hg).
An interesting finding in the study was that effective orifice area and indexed effective orifice area both increased significantly during exercise with a mechanical prosthesis, but did not increase at all with a biologic prosthesis (2.2 vs. 1.8 cm2; 1.57 vs. 1.18 cm2/m2, respectively), said Dr. Fino of Azienda Ospedaliera Papa Giovanni XXIII, in Bergamo, Italy.
“We can’t explain why this effective area does not increase with the bioprosthesis,” he said.
The findings have not changed the center’s clinical approach, but warrant bigger, longer confirmatory studies, he said.
Dr. Fino and his coauthors reported having no relevant financial disclosures.
CHICAGO – Biologic prostheses in patients with severe ischemic mitral regurgitation undergoing mitral valve replacement were associated with worse valve hemodynamics and decreased functional capacity, compared with mechanical prostheses, long-term follow-up data showed.
Dr. Carlo Fino reported the results of a retrospective study involving 86 consecutive patients who received mitral valve replacement with either biologic (41) or mechanical (45) prostheses for chronic ischemic mitral valve regurgitation. Their mean age was 63 years and 60 were male.
Significantly more patients with mechanical bioprostheses had a history of heart failure (53% vs. 27%), but all other baseline demographic, clinical, and echocardiographic data were similar. Patients with atrial fibrillation were excluded from the study.
Operative variables were also similar between the mechanical and biologic groups including cardiopulmonary bypass time (mean, 85 vs. 82 minutes), aortic cross clamp time (mean, 71 vs. 68 minutes), arterial grafts per patient (1.2 for both groups), anastomoses per patient (2.7 vs. 2.4), and use of intra-aortic balloon pump (2 patients vs. 1 patient).
At 32 months’ follow-up, patients with mechanical versus biologic prostheses had significantly higher left ventricular ejection fraction (49% vs. 42%) and cardiac index (4.8 vs. 4.5 L/min per square meter) during exercise, Dr. Fino reported at the American Heart Association scientific sessions.
Systolic pulmonary arterial pressure increased modestly during exercise with a mechanical valve, but was significantly higher with a biologic valve (41 vs. 59 mm Hg), as was mitral peak gradient (11.26 vs. 16 mm Hg).
An interesting finding in the study was that effective orifice area and indexed effective orifice area both increased significantly during exercise with a mechanical prosthesis, but did not increase at all with a biologic prosthesis (2.2 vs. 1.8 cm2; 1.57 vs. 1.18 cm2/m2, respectively), said Dr. Fino of Azienda Ospedaliera Papa Giovanni XXIII, in Bergamo, Italy.
“We can’t explain why this effective area does not increase with the bioprosthesis,” he said.
The findings have not changed the center’s clinical approach, but warrant bigger, longer confirmatory studies, he said.
Dr. Fino and his coauthors reported having no relevant financial disclosures.
CHICAGO – Biologic prostheses in patients with severe ischemic mitral regurgitation undergoing mitral valve replacement were associated with worse valve hemodynamics and decreased functional capacity, compared with mechanical prostheses, long-term follow-up data showed.
Dr. Carlo Fino reported the results of a retrospective study involving 86 consecutive patients who received mitral valve replacement with either biologic (41) or mechanical (45) prostheses for chronic ischemic mitral valve regurgitation. Their mean age was 63 years and 60 were male.
Significantly more patients with mechanical bioprostheses had a history of heart failure (53% vs. 27%), but all other baseline demographic, clinical, and echocardiographic data were similar. Patients with atrial fibrillation were excluded from the study.
Operative variables were also similar between the mechanical and biologic groups including cardiopulmonary bypass time (mean, 85 vs. 82 minutes), aortic cross clamp time (mean, 71 vs. 68 minutes), arterial grafts per patient (1.2 for both groups), anastomoses per patient (2.7 vs. 2.4), and use of intra-aortic balloon pump (2 patients vs. 1 patient).
At 32 months’ follow-up, patients with mechanical versus biologic prostheses had significantly higher left ventricular ejection fraction (49% vs. 42%) and cardiac index (4.8 vs. 4.5 L/min per square meter) during exercise, Dr. Fino reported at the American Heart Association scientific sessions.
Systolic pulmonary arterial pressure increased modestly during exercise with a mechanical valve, but was significantly higher with a biologic valve (41 vs. 59 mm Hg), as was mitral peak gradient (11.26 vs. 16 mm Hg).
An interesting finding in the study was that effective orifice area and indexed effective orifice area both increased significantly during exercise with a mechanical prosthesis, but did not increase at all with a biologic prosthesis (2.2 vs. 1.8 cm2; 1.57 vs. 1.18 cm2/m2, respectively), said Dr. Fino of Azienda Ospedaliera Papa Giovanni XXIII, in Bergamo, Italy.
“We can’t explain why this effective area does not increase with the bioprosthesis,” he said.
The findings have not changed the center’s clinical approach, but warrant bigger, longer confirmatory studies, he said.
Dr. Fino and his coauthors reported having no relevant financial disclosures.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Patients with severe mitral valve regurgitation implanted with a mechanical prosthesis appear to have better cardiovascular performance in the long term than those given biologic prostheses.
Major finding: Indexed effective orifice area increased significantly during exercise with a mechanical prosthesis versus a biologic one (1.57 vs. 1.18 cm2/m2).
Data source: A retrospective study in 86 consecutive patients undergoing mitral valve replacement for severe ischemic mitral regurgitation.
Disclosures: Dr. Fino and his coauthors reported having no relevant financial disclosures.
Ofatumumab maintenance halves risk of progression in relapsed CLL
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
AT ASH 2014
Key clinical point: Maintenance ofatumumab cuts the risk of progression in half among patients with relapsed CLL.
Major finding: Progression-free survival was 15.2 months with observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Data source: Randomized phase III trial in 474 patients with relapsed CLL.
Disclosures: GlaxoSmithKline sponsored the study. Dr. van Oers reported having no financial disclosures.
Brentuximab changes landscape for post-transplant Hodgkin’s lymphoma patients
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
AT ASH 2014
Key clinical point: Brentuximab vedotin given immediately post-transplant significantly improves progression-free survival in patients with Hodgkin’s lymphoma at high risk for progression.
Major finding: Median progression-free survival per independent review was 24 months with placebo vs. 43 months with brentuximab (HR, 0.57; P = .001).
Data source: Randomized, double-blind, phase III study in 329 patients with Hodgkin’s lymphoma.
Disclosures: Seattle Genetics sponsored the study. Dr. Moskowitz reported research funding from Genentech and Merck, and research funding from and consultancy for Seattle Genetics. Several co-authors reported financial ties with industry, including employment with or equity ownership in Seattle Genetics.
