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Tumor-treating fields may improve outcomes in glioblastoma
Patients with glioblastoma who underwent standard chemoradiotherapy followed by maintenance therapy with tumor-treating fields plus temozolomide had significantly longer progression-free and overall survival, compared with temozolomide maintenance monotherapy, according to a recent report.
In the intent-to-treat population, median progression-free survival (PFS) for tumor-treating fields (TTFields) plus temozolomide was 7.1 months, compared with 4.0 months for temozolomide alone (hazard ratio, 0.62; 98.7% confidence interval, 0.43-0.89; P = .001). Overall survival (OS) in the per-protocol population, a prespecified secondary endpoint, was also significantly increased (20.5 months vs. 15.6 months; HR, 0.64; 99.4% CI, 0.42-0.98; P = .004), prompting early termination of the study that allowed patients in the control group the option to receive TTFields.
The prognosis for glioblastoma remains poor for this highly aggressive brain tumor, with no major treatment advance in more than a decade, according to Dr. Roger Stupp, chairman of the department of oncology and the Cancer Center at the University of Zürich Hospital and his colleagues.
“In the interim analysis of this randomized clinical trial, the addition of TTFields to standard maintenance temozolomide significantly improved progression-free and overall survival,” they wrote (JAMA. 2015;314[23]:2535-43. doi: 10.1001/jama.2015.16669).
TTFields are low-intensity, intermediate-frequency alternating electric fields delivered via transducer arrays applied to the shaved scalp. The treatment is hypothesized to disrupt spindle formation during cell division, leading to mitotic arrest and apoptosis.
The multicenter trial enrolled 695 patients with newly diagnosed glioblastoma randomized 2:1 to receive TTFields plus temozolomide or temozolomide alone as maintenance therapy from 2009 to 2014. Interim analysis included 210 patients in the TTFields plus temozolomide group and 105 patients in the temozolomide alone group. The median number of temozolomide cycles until evidence of tumor progression was six cycles for the TTFields group, compared with four cycles for the temozolomide-alone group.
The median time from diagnosis to randomization was 3.8 months. When added to the median PFS of 4 months for the control group of this study, the median 7.8-month PFS is similar to most other reports.
The addition of TTFields to treatment was not associated with significant increase in systemic toxicity, except for higher incidences of scalp irritation, anxiety, confusion, insomnia, and headaches. Seizure rates did not increase.
Because a sham treatment for the control group was deemed impractical, the study was open-label, which raises the question of a placebo effect. The magnitude of the effect size (HR, 0.62 for PFS and 0.74 for OS) is greater than what could be attributed to a placebo effect, according to the investigators.
The trial was sponsored by Novocure, which markets the TTFields device. Dr. Stupp reported having consulting or advisory with Novocure, Roche/Genentech, Merck KGaA, Merck and Co, and Novartis. Several of his coauthors reported ties to industry.
Results of the study by Dr. Stupp and his colleagues are the first in a decade to demonstrate an improvement in survival for patients with glioblastoma. As a result, the Food and Drug Administration recently approved the therapy, which carries a cost of $20,000 per month. However, several aspects of the study warrant further analysis.
Since the study was not blinded or placebo-controlled, the placebo effect cannot be assessed. Although placebos are rarely associated with tumor responses in well-designed trials, patients who take only placebos reliably live longer than those who do not, possibly because of adherence bias. Adherent patients likely exhibit other healthy behaviors that can produce significant survival advantages, and some studies show adherence as one of the strongest independent variables influencing outcome. This study does not distinguish whether the survival benefit associated with the use of TTFields was because of the efficacy of the device or from adherence bias.
Another confounding factor was that patients in the temozolomide-alone group received less adjuvant chemotherapy (median four cycles before tumor progression), compared with the TTFields group (six cycles). Potentially assuming that the device would work, patients and physicians could have minimized symptoms or signs of tumor recurrence. This would have prolonged the use of temozolomide, an effective chemotherapy for glioblastoma. (Increased exposure to temozolomide in a similar patient population, however, produced no increase in survival.)
The mechanism by which TTFields leverage chemotherapy to treat tumors remains unclear. Given the survival benefit reported in this study, determining the scientific basis for efficacy of the method becomes a priority. Perhaps most concerning are the doubts, as a result of the study design chosen, about the true efficacy of the therapy.
Dr. John H. Sampson is a professor of surgery in the neurosurgery department at Duke University, Durham, N.C. These remarks were part of an editorial accompanying the report (JAMA. 2015;314[23];2511-13. doi: 10.1001/jama.2015.16701). Dr. Sampson reported ties to Celldex Therapeutics, Brainlab, and Bristol-Myers Squibb, as well as holding unrelated patents with Celldex and Annias Immunotherapeutics.
Results of the study by Dr. Stupp and his colleagues are the first in a decade to demonstrate an improvement in survival for patients with glioblastoma. As a result, the Food and Drug Administration recently approved the therapy, which carries a cost of $20,000 per month. However, several aspects of the study warrant further analysis.
Since the study was not blinded or placebo-controlled, the placebo effect cannot be assessed. Although placebos are rarely associated with tumor responses in well-designed trials, patients who take only placebos reliably live longer than those who do not, possibly because of adherence bias. Adherent patients likely exhibit other healthy behaviors that can produce significant survival advantages, and some studies show adherence as one of the strongest independent variables influencing outcome. This study does not distinguish whether the survival benefit associated with the use of TTFields was because of the efficacy of the device or from adherence bias.
Another confounding factor was that patients in the temozolomide-alone group received less adjuvant chemotherapy (median four cycles before tumor progression), compared with the TTFields group (six cycles). Potentially assuming that the device would work, patients and physicians could have minimized symptoms or signs of tumor recurrence. This would have prolonged the use of temozolomide, an effective chemotherapy for glioblastoma. (Increased exposure to temozolomide in a similar patient population, however, produced no increase in survival.)
The mechanism by which TTFields leverage chemotherapy to treat tumors remains unclear. Given the survival benefit reported in this study, determining the scientific basis for efficacy of the method becomes a priority. Perhaps most concerning are the doubts, as a result of the study design chosen, about the true efficacy of the therapy.
Dr. John H. Sampson is a professor of surgery in the neurosurgery department at Duke University, Durham, N.C. These remarks were part of an editorial accompanying the report (JAMA. 2015;314[23];2511-13. doi: 10.1001/jama.2015.16701). Dr. Sampson reported ties to Celldex Therapeutics, Brainlab, and Bristol-Myers Squibb, as well as holding unrelated patents with Celldex and Annias Immunotherapeutics.
Results of the study by Dr. Stupp and his colleagues are the first in a decade to demonstrate an improvement in survival for patients with glioblastoma. As a result, the Food and Drug Administration recently approved the therapy, which carries a cost of $20,000 per month. However, several aspects of the study warrant further analysis.
Since the study was not blinded or placebo-controlled, the placebo effect cannot be assessed. Although placebos are rarely associated with tumor responses in well-designed trials, patients who take only placebos reliably live longer than those who do not, possibly because of adherence bias. Adherent patients likely exhibit other healthy behaviors that can produce significant survival advantages, and some studies show adherence as one of the strongest independent variables influencing outcome. This study does not distinguish whether the survival benefit associated with the use of TTFields was because of the efficacy of the device or from adherence bias.
Another confounding factor was that patients in the temozolomide-alone group received less adjuvant chemotherapy (median four cycles before tumor progression), compared with the TTFields group (six cycles). Potentially assuming that the device would work, patients and physicians could have minimized symptoms or signs of tumor recurrence. This would have prolonged the use of temozolomide, an effective chemotherapy for glioblastoma. (Increased exposure to temozolomide in a similar patient population, however, produced no increase in survival.)
The mechanism by which TTFields leverage chemotherapy to treat tumors remains unclear. Given the survival benefit reported in this study, determining the scientific basis for efficacy of the method becomes a priority. Perhaps most concerning are the doubts, as a result of the study design chosen, about the true efficacy of the therapy.
Dr. John H. Sampson is a professor of surgery in the neurosurgery department at Duke University, Durham, N.C. These remarks were part of an editorial accompanying the report (JAMA. 2015;314[23];2511-13. doi: 10.1001/jama.2015.16701). Dr. Sampson reported ties to Celldex Therapeutics, Brainlab, and Bristol-Myers Squibb, as well as holding unrelated patents with Celldex and Annias Immunotherapeutics.
Patients with glioblastoma who underwent standard chemoradiotherapy followed by maintenance therapy with tumor-treating fields plus temozolomide had significantly longer progression-free and overall survival, compared with temozolomide maintenance monotherapy, according to a recent report.
In the intent-to-treat population, median progression-free survival (PFS) for tumor-treating fields (TTFields) plus temozolomide was 7.1 months, compared with 4.0 months for temozolomide alone (hazard ratio, 0.62; 98.7% confidence interval, 0.43-0.89; P = .001). Overall survival (OS) in the per-protocol population, a prespecified secondary endpoint, was also significantly increased (20.5 months vs. 15.6 months; HR, 0.64; 99.4% CI, 0.42-0.98; P = .004), prompting early termination of the study that allowed patients in the control group the option to receive TTFields.
The prognosis for glioblastoma remains poor for this highly aggressive brain tumor, with no major treatment advance in more than a decade, according to Dr. Roger Stupp, chairman of the department of oncology and the Cancer Center at the University of Zürich Hospital and his colleagues.
“In the interim analysis of this randomized clinical trial, the addition of TTFields to standard maintenance temozolomide significantly improved progression-free and overall survival,” they wrote (JAMA. 2015;314[23]:2535-43. doi: 10.1001/jama.2015.16669).
TTFields are low-intensity, intermediate-frequency alternating electric fields delivered via transducer arrays applied to the shaved scalp. The treatment is hypothesized to disrupt spindle formation during cell division, leading to mitotic arrest and apoptosis.
The multicenter trial enrolled 695 patients with newly diagnosed glioblastoma randomized 2:1 to receive TTFields plus temozolomide or temozolomide alone as maintenance therapy from 2009 to 2014. Interim analysis included 210 patients in the TTFields plus temozolomide group and 105 patients in the temozolomide alone group. The median number of temozolomide cycles until evidence of tumor progression was six cycles for the TTFields group, compared with four cycles for the temozolomide-alone group.
The median time from diagnosis to randomization was 3.8 months. When added to the median PFS of 4 months for the control group of this study, the median 7.8-month PFS is similar to most other reports.
The addition of TTFields to treatment was not associated with significant increase in systemic toxicity, except for higher incidences of scalp irritation, anxiety, confusion, insomnia, and headaches. Seizure rates did not increase.
Because a sham treatment for the control group was deemed impractical, the study was open-label, which raises the question of a placebo effect. The magnitude of the effect size (HR, 0.62 for PFS and 0.74 for OS) is greater than what could be attributed to a placebo effect, according to the investigators.
The trial was sponsored by Novocure, which markets the TTFields device. Dr. Stupp reported having consulting or advisory with Novocure, Roche/Genentech, Merck KGaA, Merck and Co, and Novartis. Several of his coauthors reported ties to industry.
Patients with glioblastoma who underwent standard chemoradiotherapy followed by maintenance therapy with tumor-treating fields plus temozolomide had significantly longer progression-free and overall survival, compared with temozolomide maintenance monotherapy, according to a recent report.
In the intent-to-treat population, median progression-free survival (PFS) for tumor-treating fields (TTFields) plus temozolomide was 7.1 months, compared with 4.0 months for temozolomide alone (hazard ratio, 0.62; 98.7% confidence interval, 0.43-0.89; P = .001). Overall survival (OS) in the per-protocol population, a prespecified secondary endpoint, was also significantly increased (20.5 months vs. 15.6 months; HR, 0.64; 99.4% CI, 0.42-0.98; P = .004), prompting early termination of the study that allowed patients in the control group the option to receive TTFields.
The prognosis for glioblastoma remains poor for this highly aggressive brain tumor, with no major treatment advance in more than a decade, according to Dr. Roger Stupp, chairman of the department of oncology and the Cancer Center at the University of Zürich Hospital and his colleagues.
“In the interim analysis of this randomized clinical trial, the addition of TTFields to standard maintenance temozolomide significantly improved progression-free and overall survival,” they wrote (JAMA. 2015;314[23]:2535-43. doi: 10.1001/jama.2015.16669).
TTFields are low-intensity, intermediate-frequency alternating electric fields delivered via transducer arrays applied to the shaved scalp. The treatment is hypothesized to disrupt spindle formation during cell division, leading to mitotic arrest and apoptosis.
The multicenter trial enrolled 695 patients with newly diagnosed glioblastoma randomized 2:1 to receive TTFields plus temozolomide or temozolomide alone as maintenance therapy from 2009 to 2014. Interim analysis included 210 patients in the TTFields plus temozolomide group and 105 patients in the temozolomide alone group. The median number of temozolomide cycles until evidence of tumor progression was six cycles for the TTFields group, compared with four cycles for the temozolomide-alone group.
The median time from diagnosis to randomization was 3.8 months. When added to the median PFS of 4 months for the control group of this study, the median 7.8-month PFS is similar to most other reports.
The addition of TTFields to treatment was not associated with significant increase in systemic toxicity, except for higher incidences of scalp irritation, anxiety, confusion, insomnia, and headaches. Seizure rates did not increase.
Because a sham treatment for the control group was deemed impractical, the study was open-label, which raises the question of a placebo effect. The magnitude of the effect size (HR, 0.62 for PFS and 0.74 for OS) is greater than what could be attributed to a placebo effect, according to the investigators.
The trial was sponsored by Novocure, which markets the TTFields device. Dr. Stupp reported having consulting or advisory with Novocure, Roche/Genentech, Merck KGaA, Merck and Co, and Novartis. Several of his coauthors reported ties to industry.
FROM JAMA
Key clinical point: Maintenance therapy with tumor-treating fields (TTFields) plus temozolomide resulted in longer survival, compared with temozolomide alone, for patients with glioblastoma.
Major finding: Median progression-free survival for TTFields plus temozolomide was 7.1 months, compared with 4.0 months for temozolomide alone (HR, 0.62; 98.7% CI, 0.43-0.89; P = .001).
Data sources: Interim analysis of the randomized trial included 210 patients in the TTFields plus temozolomide group and 105 patients in the temozolomide alone group.
Disclosures: The trial was sponsored by Novocure, which markets the TTFields device. Dr. Stupp reported having consulting or advisory with Novocure, Roche/Genentech, Merck KGaA, Merck, and Novartis. Several of his coauthors reported ties to industry.
Predictors for Surgical Management of Small Bowel Obstruction
Clinical question: Are there clinical or computerized tomography (CT) findings that identify which patients will need early surgical management in adhesive small bowel obstruction (ASBO)?
Background: Previous studies determined adverse outcomes resulting from delayed surgery in patients with ASBO: increased length of stay (LOS), complications, and mortality. Most patients respond to nonoperative management, however.
Study design: Prospective observational study.
Setting: Three academic and tertiary referral medical centers.
Synopsis: Using multivariate analysis of 202 patients admitted with presumed adhesive ASBO without immediate surgical need, of whom 52 required eventual surgical intervention, this study found three predictors for needing operative care: no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; P=0.003), as well as the CT findings of a high-grade obstruction, defined as only minimal passage of air and fluid into the distal small bowel or colon (OR, 2.44; 95% CI, 1.10-5.43; P=0.028) or the presence of free fluid (OR, 2.59; 95% CI, 1.13-5.90; P=0.023).
Despite these associations, clinicians should not view these findings as indications for surgery. Of the patients who responded to nonoperative management, one-third had no flatus, and on CT one-third had high-grade obstruction and half had free fluid. Instead, because patients with these findings are at an increased risk of failing nonoperative management, they should be observed more closely and reassessed more frequently.
Bottom line: Patients without flatus or with the presence of free fluid or high-grade obstruction on CT are at an increased risk of requiring surgical management for ASBO.
Citation: Kulvatunyou N, Pandit V, Moutamn S, et al. A multi-institution prospective observational study of small bowel obstruction: clinical and computerized tomography predictors of which patients may require early surgery. J Trauma Acute Care Surg. 2015;79(3):393-398.
Clinical question: Are there clinical or computerized tomography (CT) findings that identify which patients will need early surgical management in adhesive small bowel obstruction (ASBO)?
Background: Previous studies determined adverse outcomes resulting from delayed surgery in patients with ASBO: increased length of stay (LOS), complications, and mortality. Most patients respond to nonoperative management, however.
Study design: Prospective observational study.
Setting: Three academic and tertiary referral medical centers.
Synopsis: Using multivariate analysis of 202 patients admitted with presumed adhesive ASBO without immediate surgical need, of whom 52 required eventual surgical intervention, this study found three predictors for needing operative care: no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; P=0.003), as well as the CT findings of a high-grade obstruction, defined as only minimal passage of air and fluid into the distal small bowel or colon (OR, 2.44; 95% CI, 1.10-5.43; P=0.028) or the presence of free fluid (OR, 2.59; 95% CI, 1.13-5.90; P=0.023).
Despite these associations, clinicians should not view these findings as indications for surgery. Of the patients who responded to nonoperative management, one-third had no flatus, and on CT one-third had high-grade obstruction and half had free fluid. Instead, because patients with these findings are at an increased risk of failing nonoperative management, they should be observed more closely and reassessed more frequently.
Bottom line: Patients without flatus or with the presence of free fluid or high-grade obstruction on CT are at an increased risk of requiring surgical management for ASBO.
Citation: Kulvatunyou N, Pandit V, Moutamn S, et al. A multi-institution prospective observational study of small bowel obstruction: clinical and computerized tomography predictors of which patients may require early surgery. J Trauma Acute Care Surg. 2015;79(3):393-398.
Clinical question: Are there clinical or computerized tomography (CT) findings that identify which patients will need early surgical management in adhesive small bowel obstruction (ASBO)?
Background: Previous studies determined adverse outcomes resulting from delayed surgery in patients with ASBO: increased length of stay (LOS), complications, and mortality. Most patients respond to nonoperative management, however.
Study design: Prospective observational study.
Setting: Three academic and tertiary referral medical centers.
Synopsis: Using multivariate analysis of 202 patients admitted with presumed adhesive ASBO without immediate surgical need, of whom 52 required eventual surgical intervention, this study found three predictors for needing operative care: no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; P=0.003), as well as the CT findings of a high-grade obstruction, defined as only minimal passage of air and fluid into the distal small bowel or colon (OR, 2.44; 95% CI, 1.10-5.43; P=0.028) or the presence of free fluid (OR, 2.59; 95% CI, 1.13-5.90; P=0.023).
Despite these associations, clinicians should not view these findings as indications for surgery. Of the patients who responded to nonoperative management, one-third had no flatus, and on CT one-third had high-grade obstruction and half had free fluid. Instead, because patients with these findings are at an increased risk of failing nonoperative management, they should be observed more closely and reassessed more frequently.
Bottom line: Patients without flatus or with the presence of free fluid or high-grade obstruction on CT are at an increased risk of requiring surgical management for ASBO.
Citation: Kulvatunyou N, Pandit V, Moutamn S, et al. A multi-institution prospective observational study of small bowel obstruction: clinical and computerized tomography predictors of which patients may require early surgery. J Trauma Acute Care Surg. 2015;79(3):393-398.
Adding Advanced Molecular Techniques to Standard Blood Cultures May Improve Patient Outcomes
Clinical question: Does the addition of rapid multiplex polymerase chain reaction molecular techniques to standard blood culture bottle (BCB) processing, with or without antimicrobial stewardship recommendations, affect antimicrobial utilization and patient outcomes?
Background: Standard BCB processing typically requires two days to provide identification and susceptibility testing results. PCR-based molecular testing is available to test positive BCB and deliver specific susceptibility results more rapidly, typically within one hour. Earlier results could improve antimicrobial utilization, limit antimicrobial resistance, decrease the risk of Clostridium difficile colitis, improve patient outcomes, and decrease healthcare costs. The impact of these techniques on outcomes is uncertain.
Study design: Prospective, randomized controlled trial (RCT).
Setting: Single large tertiary academic medical center.
Synopsis: Nearly 750 patients were randomized to conventional BCB processing (control), BCB with rapid multiplex PCR and templated recommendations (rmPCR), or BCB with rapid multiplex PCR and real-time antimicrobial stewardship provided by an infectious disease physician or specially trained pharmacist (rmPCR/AS). Time to microorganism identification was reduced from 22.3 hours in the control arm to 1.3 hours in the intervention arms. Both intervention groups had decreased use of broad spectrum piperacillin-tazobactam, increased use of narrow spectrum β-lactam, and decreased treatment of contaminants. Time to appropriate empiric treatment modification was shortest in the rmPCR/AS group.
Groups did not differ in mortality, length of stay, or cost, although an adequately powered study may show beneficial effects in these outcomes.
Bottom line: The addition of rapid multiplex PCR, ideally combined with antimicrobial stewardship, improves antimicrobial utilization in patients with positive blood cultures.
Citation: Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080.
Clinical question: Does the addition of rapid multiplex polymerase chain reaction molecular techniques to standard blood culture bottle (BCB) processing, with or without antimicrobial stewardship recommendations, affect antimicrobial utilization and patient outcomes?
Background: Standard BCB processing typically requires two days to provide identification and susceptibility testing results. PCR-based molecular testing is available to test positive BCB and deliver specific susceptibility results more rapidly, typically within one hour. Earlier results could improve antimicrobial utilization, limit antimicrobial resistance, decrease the risk of Clostridium difficile colitis, improve patient outcomes, and decrease healthcare costs. The impact of these techniques on outcomes is uncertain.
Study design: Prospective, randomized controlled trial (RCT).
Setting: Single large tertiary academic medical center.
Synopsis: Nearly 750 patients were randomized to conventional BCB processing (control), BCB with rapid multiplex PCR and templated recommendations (rmPCR), or BCB with rapid multiplex PCR and real-time antimicrobial stewardship provided by an infectious disease physician or specially trained pharmacist (rmPCR/AS). Time to microorganism identification was reduced from 22.3 hours in the control arm to 1.3 hours in the intervention arms. Both intervention groups had decreased use of broad spectrum piperacillin-tazobactam, increased use of narrow spectrum β-lactam, and decreased treatment of contaminants. Time to appropriate empiric treatment modification was shortest in the rmPCR/AS group.
Groups did not differ in mortality, length of stay, or cost, although an adequately powered study may show beneficial effects in these outcomes.
Bottom line: The addition of rapid multiplex PCR, ideally combined with antimicrobial stewardship, improves antimicrobial utilization in patients with positive blood cultures.
Citation: Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080.
Clinical question: Does the addition of rapid multiplex polymerase chain reaction molecular techniques to standard blood culture bottle (BCB) processing, with or without antimicrobial stewardship recommendations, affect antimicrobial utilization and patient outcomes?
Background: Standard BCB processing typically requires two days to provide identification and susceptibility testing results. PCR-based molecular testing is available to test positive BCB and deliver specific susceptibility results more rapidly, typically within one hour. Earlier results could improve antimicrobial utilization, limit antimicrobial resistance, decrease the risk of Clostridium difficile colitis, improve patient outcomes, and decrease healthcare costs. The impact of these techniques on outcomes is uncertain.
Study design: Prospective, randomized controlled trial (RCT).
Setting: Single large tertiary academic medical center.
Synopsis: Nearly 750 patients were randomized to conventional BCB processing (control), BCB with rapid multiplex PCR and templated recommendations (rmPCR), or BCB with rapid multiplex PCR and real-time antimicrobial stewardship provided by an infectious disease physician or specially trained pharmacist (rmPCR/AS). Time to microorganism identification was reduced from 22.3 hours in the control arm to 1.3 hours in the intervention arms. Both intervention groups had decreased use of broad spectrum piperacillin-tazobactam, increased use of narrow spectrum β-lactam, and decreased treatment of contaminants. Time to appropriate empiric treatment modification was shortest in the rmPCR/AS group.
Groups did not differ in mortality, length of stay, or cost, although an adequately powered study may show beneficial effects in these outcomes.
Bottom line: The addition of rapid multiplex PCR, ideally combined with antimicrobial stewardship, improves antimicrobial utilization in patients with positive blood cultures.
Citation: Banerjee R, Teng CB, Cunningham SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. Clin Infect Dis. 2015;61(7):1071-1080.
Osteoarticular pain affects CML patients stopping TKI
Photo courtesy of ASH
ORLANDO, FL—Cases of musculoskeletal pain have been reported after patients stop taking tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
TKI discontinuation trials—notably, the STOP imatinib (STIM) trials and EURO-SKI trial—have been conducted to assess the feasibility of maintaining molecular remission once patients discontinue a TKI.
However, none of the studies collected low-grade events before or after patients discontinued TKI therapy.
So investigators collected data from the STIM2 study and EUROSKI trial and recorded all events from the time of TKI discontinuation.
They discovered that about 23% of patients who stopped TKI therapy experienced a withdrawal syndrome (WS) consisting largely of musculoskeletal pain, regardless of the TKI they were taking.
Philippe Rousselot, MD, PhD, of University of Versailles St-Quentin-en-Yvelines, Versailles, France, discussed this finding at the 2015 ASH Annual Meeting as abstract 137.*
Dr Rousselot noted that investigators first reported the TKI WS in 2014 in CML patients enrolled on the EURO-SKI trial who were discontinuing imatinib (Richter et al, JCO 2014).
A team of French investigators undertook the current observational study to estimate the prevalence of the WS and to identify clinical factors associated with it.
They collected, prospectively, the adverse events from all 428 French patients who were enrolled in the STIM2 (n=204) and EURO-SKI (n=224) trials. And they compared patients who stopped taking TKIs and had a painful WS to those who stopped TKIs and did not have a painful syndrome.
Patient characteristics
Patient characteristics were well balanced between the STIM2 and EURO-SKI groups, with the exception of the median time on TKI before discontinuation. In the STIM2 group, patients were a median of 77.4 months on TKI therapy. In the EURO-SKI group, the median time on a TKI was 100.4 months (P<0.001).
In all, there were 208 male and 220 female patients included. They were a median age of 64 (range, 53–73) and 63 (range, 53–70) years in the STIM2 and EURO-SKI groups, respectively.
Sokal scores were also comparable between the cohorts, with most patients falling in the low and intermediate ranges.
Prevalence and characteristics of WS
Overall, 326 patients (76.2%) were without WS and 102 (23.8%) had WS. In the STIM2 cohort, 193 patients (86.2%) were without WS and 31 (13.8%) had WS. In the EURO-SKI cohort, 133 patients (65.2%) were without WS and 71 (34.8%) had WS.
“And these differences [between cohorts] are significant,” Dr Rousselot pointed out.
Investigators analyzed clinical characteristics of WS in 40 patients and determined that the median time from TKI discontinuation to WS was 21 days, and the median duration of WS was 7 months (range, 3–30).
Pain was located in the shoulder and spine for 67% of the patients and elsewhere in 33%. About two-thirds of patients (62.5%) experienced grade 1–2 pain, and 37.5% experienced grade 3–4 pain.
Nineteen patients resumed TKI therapy, “because of loss of MMR [major molecular response] or loss of clinical response,” Dr Rousselot said.
And the pain disappeared in 52.6% of them when they resumed TKI therapy. The median duration of TKI therapy before WS pain disappeared was 3 weeks.
Risk factors for WS
Investigators determined that CML duration, time on a TKI, and previous history of osteoarticular symptoms were risk factors for WS.
Patients without WS had CML for a shorter time—a mean of 8.7 ± 3.1 months, compared to 9.7 ± 3.8 for those with WS (P=0.02).
Patients without WS were also on a TKI for a shorter time—a median of 81.2 months (range, 61.2–108.0), compared to 97.3 months (range, 73.7–122.9) for those with WS (P<0.001).
Patients with a previous history of osteoarticular symptoms were more likely to experience WS—22.9%, compared to 9.8% without a previous history (P=0.002).
Most patients were receiving imatinib—323 without WS and 100 with WS. The 1 patient receiving dasatinib had no WS. And of the 4 patients receiving nilotinib, 2 had WS and 2 didn’t.
And so the type of TKI therapy—dasatinib, imatinib, or nilotinib—was not significant (P=0.42).
Investigators performed a multivariate analysis adjusted for gender, CML duration, and Sokal score, and 2 risk factors emerged: previous history of osteoarticular symptoms (relative risk: 2.08) and time on TKI (relative risk: 2.23).
Discussion
Dr Rousselot compared the Richter trial (Richter et al, JCO 2014) to the current study and noted that the Richter trial, with an enrollment of 50 patients, had a WS prevalence of 30%. But the current trial had a prevalence of 24%.
The difference in WS may be due to time on TKI, Dr Rousselot said, as patients in the Richter trial were on TKI treatment for a longer period of time.
“The time of onset is the same [in both trials],” Dr Rousselot said, as are the TKI used, location of pain, and duration of pain.
“So what we can say is [with] shorter TKI treatment . . . , we have a higher risk of molecular relapse but a lower risk of withdrawal syndrome.”
And with longer TKI treatment, the converse appears to be true. It reduces the risk of molecular relapse but raises the risk of withdrawal syndrome. 
*Data in the abstract differ from the presentation.
Photo courtesy of ASH
ORLANDO, FL—Cases of musculoskeletal pain have been reported after patients stop taking tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
TKI discontinuation trials—notably, the STOP imatinib (STIM) trials and EURO-SKI trial—have been conducted to assess the feasibility of maintaining molecular remission once patients discontinue a TKI.
However, none of the studies collected low-grade events before or after patients discontinued TKI therapy.
So investigators collected data from the STIM2 study and EUROSKI trial and recorded all events from the time of TKI discontinuation.
They discovered that about 23% of patients who stopped TKI therapy experienced a withdrawal syndrome (WS) consisting largely of musculoskeletal pain, regardless of the TKI they were taking.
Philippe Rousselot, MD, PhD, of University of Versailles St-Quentin-en-Yvelines, Versailles, France, discussed this finding at the 2015 ASH Annual Meeting as abstract 137.*
Dr Rousselot noted that investigators first reported the TKI WS in 2014 in CML patients enrolled on the EURO-SKI trial who were discontinuing imatinib (Richter et al, JCO 2014).
A team of French investigators undertook the current observational study to estimate the prevalence of the WS and to identify clinical factors associated with it.
They collected, prospectively, the adverse events from all 428 French patients who were enrolled in the STIM2 (n=204) and EURO-SKI (n=224) trials. And they compared patients who stopped taking TKIs and had a painful WS to those who stopped TKIs and did not have a painful syndrome.
Patient characteristics
Patient characteristics were well balanced between the STIM2 and EURO-SKI groups, with the exception of the median time on TKI before discontinuation. In the STIM2 group, patients were a median of 77.4 months on TKI therapy. In the EURO-SKI group, the median time on a TKI was 100.4 months (P<0.001).
In all, there were 208 male and 220 female patients included. They were a median age of 64 (range, 53–73) and 63 (range, 53–70) years in the STIM2 and EURO-SKI groups, respectively.
Sokal scores were also comparable between the cohorts, with most patients falling in the low and intermediate ranges.
Prevalence and characteristics of WS
Overall, 326 patients (76.2%) were without WS and 102 (23.8%) had WS. In the STIM2 cohort, 193 patients (86.2%) were without WS and 31 (13.8%) had WS. In the EURO-SKI cohort, 133 patients (65.2%) were without WS and 71 (34.8%) had WS.
“And these differences [between cohorts] are significant,” Dr Rousselot pointed out.
Investigators analyzed clinical characteristics of WS in 40 patients and determined that the median time from TKI discontinuation to WS was 21 days, and the median duration of WS was 7 months (range, 3–30).
Pain was located in the shoulder and spine for 67% of the patients and elsewhere in 33%. About two-thirds of patients (62.5%) experienced grade 1–2 pain, and 37.5% experienced grade 3–4 pain.
Nineteen patients resumed TKI therapy, “because of loss of MMR [major molecular response] or loss of clinical response,” Dr Rousselot said.
And the pain disappeared in 52.6% of them when they resumed TKI therapy. The median duration of TKI therapy before WS pain disappeared was 3 weeks.
Risk factors for WS
Investigators determined that CML duration, time on a TKI, and previous history of osteoarticular symptoms were risk factors for WS.
Patients without WS had CML for a shorter time—a mean of 8.7 ± 3.1 months, compared to 9.7 ± 3.8 for those with WS (P=0.02).
Patients without WS were also on a TKI for a shorter time—a median of 81.2 months (range, 61.2–108.0), compared to 97.3 months (range, 73.7–122.9) for those with WS (P<0.001).
Patients with a previous history of osteoarticular symptoms were more likely to experience WS—22.9%, compared to 9.8% without a previous history (P=0.002).
Most patients were receiving imatinib—323 without WS and 100 with WS. The 1 patient receiving dasatinib had no WS. And of the 4 patients receiving nilotinib, 2 had WS and 2 didn’t.
And so the type of TKI therapy—dasatinib, imatinib, or nilotinib—was not significant (P=0.42).
Investigators performed a multivariate analysis adjusted for gender, CML duration, and Sokal score, and 2 risk factors emerged: previous history of osteoarticular symptoms (relative risk: 2.08) and time on TKI (relative risk: 2.23).
Discussion
Dr Rousselot compared the Richter trial (Richter et al, JCO 2014) to the current study and noted that the Richter trial, with an enrollment of 50 patients, had a WS prevalence of 30%. But the current trial had a prevalence of 24%.
The difference in WS may be due to time on TKI, Dr Rousselot said, as patients in the Richter trial were on TKI treatment for a longer period of time.
“The time of onset is the same [in both trials],” Dr Rousselot said, as are the TKI used, location of pain, and duration of pain.
“So what we can say is [with] shorter TKI treatment . . . , we have a higher risk of molecular relapse but a lower risk of withdrawal syndrome.”
And with longer TKI treatment, the converse appears to be true. It reduces the risk of molecular relapse but raises the risk of withdrawal syndrome.
*Data in the abstract differ from the presentation.
Photo courtesy of ASH
ORLANDO, FL—Cases of musculoskeletal pain have been reported after patients stop taking tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
TKI discontinuation trials—notably, the STOP imatinib (STIM) trials and EURO-SKI trial—have been conducted to assess the feasibility of maintaining molecular remission once patients discontinue a TKI.
However, none of the studies collected low-grade events before or after patients discontinued TKI therapy.
So investigators collected data from the STIM2 study and EUROSKI trial and recorded all events from the time of TKI discontinuation.
They discovered that about 23% of patients who stopped TKI therapy experienced a withdrawal syndrome (WS) consisting largely of musculoskeletal pain, regardless of the TKI they were taking.
Philippe Rousselot, MD, PhD, of University of Versailles St-Quentin-en-Yvelines, Versailles, France, discussed this finding at the 2015 ASH Annual Meeting as abstract 137.*
Dr Rousselot noted that investigators first reported the TKI WS in 2014 in CML patients enrolled on the EURO-SKI trial who were discontinuing imatinib (Richter et al, JCO 2014).
A team of French investigators undertook the current observational study to estimate the prevalence of the WS and to identify clinical factors associated with it.
They collected, prospectively, the adverse events from all 428 French patients who were enrolled in the STIM2 (n=204) and EURO-SKI (n=224) trials. And they compared patients who stopped taking TKIs and had a painful WS to those who stopped TKIs and did not have a painful syndrome.
Patient characteristics
Patient characteristics were well balanced between the STIM2 and EURO-SKI groups, with the exception of the median time on TKI before discontinuation. In the STIM2 group, patients were a median of 77.4 months on TKI therapy. In the EURO-SKI group, the median time on a TKI was 100.4 months (P<0.001).
In all, there were 208 male and 220 female patients included. They were a median age of 64 (range, 53–73) and 63 (range, 53–70) years in the STIM2 and EURO-SKI groups, respectively.
Sokal scores were also comparable between the cohorts, with most patients falling in the low and intermediate ranges.
Prevalence and characteristics of WS
Overall, 326 patients (76.2%) were without WS and 102 (23.8%) had WS. In the STIM2 cohort, 193 patients (86.2%) were without WS and 31 (13.8%) had WS. In the EURO-SKI cohort, 133 patients (65.2%) were without WS and 71 (34.8%) had WS.
“And these differences [between cohorts] are significant,” Dr Rousselot pointed out.
Investigators analyzed clinical characteristics of WS in 40 patients and determined that the median time from TKI discontinuation to WS was 21 days, and the median duration of WS was 7 months (range, 3–30).
Pain was located in the shoulder and spine for 67% of the patients and elsewhere in 33%. About two-thirds of patients (62.5%) experienced grade 1–2 pain, and 37.5% experienced grade 3–4 pain.
Nineteen patients resumed TKI therapy, “because of loss of MMR [major molecular response] or loss of clinical response,” Dr Rousselot said.
And the pain disappeared in 52.6% of them when they resumed TKI therapy. The median duration of TKI therapy before WS pain disappeared was 3 weeks.
Risk factors for WS
Investigators determined that CML duration, time on a TKI, and previous history of osteoarticular symptoms were risk factors for WS.
Patients without WS had CML for a shorter time—a mean of 8.7 ± 3.1 months, compared to 9.7 ± 3.8 for those with WS (P=0.02).
Patients without WS were also on a TKI for a shorter time—a median of 81.2 months (range, 61.2–108.0), compared to 97.3 months (range, 73.7–122.9) for those with WS (P<0.001).
Patients with a previous history of osteoarticular symptoms were more likely to experience WS—22.9%, compared to 9.8% without a previous history (P=0.002).
Most patients were receiving imatinib—323 without WS and 100 with WS. The 1 patient receiving dasatinib had no WS. And of the 4 patients receiving nilotinib, 2 had WS and 2 didn’t.
And so the type of TKI therapy—dasatinib, imatinib, or nilotinib—was not significant (P=0.42).
Investigators performed a multivariate analysis adjusted for gender, CML duration, and Sokal score, and 2 risk factors emerged: previous history of osteoarticular symptoms (relative risk: 2.08) and time on TKI (relative risk: 2.23).
Discussion
Dr Rousselot compared the Richter trial (Richter et al, JCO 2014) to the current study and noted that the Richter trial, with an enrollment of 50 patients, had a WS prevalence of 30%. But the current trial had a prevalence of 24%.
The difference in WS may be due to time on TKI, Dr Rousselot said, as patients in the Richter trial were on TKI treatment for a longer period of time.
“The time of onset is the same [in both trials],” Dr Rousselot said, as are the TKI used, location of pain, and duration of pain.
“So what we can say is [with] shorter TKI treatment . . . , we have a higher risk of molecular relapse but a lower risk of withdrawal syndrome.”
And with longer TKI treatment, the converse appears to be true. It reduces the risk of molecular relapse but raises the risk of withdrawal syndrome.
*Data in the abstract differ from the presentation.
Fear really does curdle blood, study suggests
Photo by Graham Colm
Horror movies may actually be “blood-curdling,” according to a study published in The BMJ.
The research showed that watching a scary movie was associated with an increase in the clotting protein factor VIII (FVIII).
Study subjects were more likely to experience an increase in FVIII while watching a horror film than an educational film.
So using the term “blood-curdling” to describe feeling extreme fear may be justified, researchers said.
The term dates back to medieval times and is based on the concept that fear would “run the blood cold” or “curdle” the blood, but the validity of this theory has never been studied.
So Banne Nemeth, MD, of Leiden University Medical Centre in The Netherlands, and his colleagues set out to assess whether acute fear can curdle blood.
Their study involved 24 healthy volunteers age 30 or younger. Fourteen subjects were assigned to watch a frightening movie followed by a non-threatening educational movie, and 10 were assigned to watch the movies in reverse order.
The movies were viewed more than a week apart at the same time of day and in a comfortable and relaxed environment. Both lasted approximately 90 minutes.
Before and after each movie (within 15 minutes), blood samples were taken and analyzed for markers of clotting activity.
After each movie, participants rated the fear they experienced using a visual analogue fear scale ranging from 0 (no fear at all) to 10 (worst fear imaginable). They also reported whether they had already seen the movie and completed a general questionnaire on lifestyle and favorite movie genre.
The horror movie was perceived to be more frightening than the educational movie, with a 5.4 mean difference in fear rating scores.
The difference in FVIII levels before and after watching the movies was higher for the horror movie than for the educational movie. The mean difference of differences was 11.1 IU/dL (95% confidence interval: 1.2 to 21.0 IU/dL).
FVIII levels increased in 12 (57%) subjects during the horror movie and in 3 (14%) during the educational movie. FVIII levels decreased in 18 (86%) participants during the educational movie and in 9 (43%) during the horror movie.
However, the researchers found no effect of either movie on thrombin-antithrombin complexes, D-dimer, or prothrombin fragments 1+2. They said this suggests that although acute fear may trigger coagulation, it does not lead to actual clot formation.
The team pointed out some study limitations but concluded that, in young and healthy adults, “watching blood-curdling movies is associated with an increase in blood coagulant factor VIII without actual thrombin formation.”
The researchers believe this phenomenon may confer an important evolutionary benefit by preparing the body for blood loss during life-threatening situations.
Photo by Graham Colm
Horror movies may actually be “blood-curdling,” according to a study published in The BMJ.
The research showed that watching a scary movie was associated with an increase in the clotting protein factor VIII (FVIII).
Study subjects were more likely to experience an increase in FVIII while watching a horror film than an educational film.
So using the term “blood-curdling” to describe feeling extreme fear may be justified, researchers said.
The term dates back to medieval times and is based on the concept that fear would “run the blood cold” or “curdle” the blood, but the validity of this theory has never been studied.
So Banne Nemeth, MD, of Leiden University Medical Centre in The Netherlands, and his colleagues set out to assess whether acute fear can curdle blood.
Their study involved 24 healthy volunteers age 30 or younger. Fourteen subjects were assigned to watch a frightening movie followed by a non-threatening educational movie, and 10 were assigned to watch the movies in reverse order.
The movies were viewed more than a week apart at the same time of day and in a comfortable and relaxed environment. Both lasted approximately 90 minutes.
Before and after each movie (within 15 minutes), blood samples were taken and analyzed for markers of clotting activity.
After each movie, participants rated the fear they experienced using a visual analogue fear scale ranging from 0 (no fear at all) to 10 (worst fear imaginable). They also reported whether they had already seen the movie and completed a general questionnaire on lifestyle and favorite movie genre.
The horror movie was perceived to be more frightening than the educational movie, with a 5.4 mean difference in fear rating scores.
The difference in FVIII levels before and after watching the movies was higher for the horror movie than for the educational movie. The mean difference of differences was 11.1 IU/dL (95% confidence interval: 1.2 to 21.0 IU/dL).
FVIII levels increased in 12 (57%) subjects during the horror movie and in 3 (14%) during the educational movie. FVIII levels decreased in 18 (86%) participants during the educational movie and in 9 (43%) during the horror movie.
However, the researchers found no effect of either movie on thrombin-antithrombin complexes, D-dimer, or prothrombin fragments 1+2. They said this suggests that although acute fear may trigger coagulation, it does not lead to actual clot formation.
The team pointed out some study limitations but concluded that, in young and healthy adults, “watching blood-curdling movies is associated with an increase in blood coagulant factor VIII without actual thrombin formation.”
The researchers believe this phenomenon may confer an important evolutionary benefit by preparing the body for blood loss during life-threatening situations.
Photo by Graham Colm
Horror movies may actually be “blood-curdling,” according to a study published in The BMJ.
The research showed that watching a scary movie was associated with an increase in the clotting protein factor VIII (FVIII).
Study subjects were more likely to experience an increase in FVIII while watching a horror film than an educational film.
So using the term “blood-curdling” to describe feeling extreme fear may be justified, researchers said.
The term dates back to medieval times and is based on the concept that fear would “run the blood cold” or “curdle” the blood, but the validity of this theory has never been studied.
So Banne Nemeth, MD, of Leiden University Medical Centre in The Netherlands, and his colleagues set out to assess whether acute fear can curdle blood.
Their study involved 24 healthy volunteers age 30 or younger. Fourteen subjects were assigned to watch a frightening movie followed by a non-threatening educational movie, and 10 were assigned to watch the movies in reverse order.
The movies were viewed more than a week apart at the same time of day and in a comfortable and relaxed environment. Both lasted approximately 90 minutes.
Before and after each movie (within 15 minutes), blood samples were taken and analyzed for markers of clotting activity.
After each movie, participants rated the fear they experienced using a visual analogue fear scale ranging from 0 (no fear at all) to 10 (worst fear imaginable). They also reported whether they had already seen the movie and completed a general questionnaire on lifestyle and favorite movie genre.
The horror movie was perceived to be more frightening than the educational movie, with a 5.4 mean difference in fear rating scores.
The difference in FVIII levels before and after watching the movies was higher for the horror movie than for the educational movie. The mean difference of differences was 11.1 IU/dL (95% confidence interval: 1.2 to 21.0 IU/dL).
FVIII levels increased in 12 (57%) subjects during the horror movie and in 3 (14%) during the educational movie. FVIII levels decreased in 18 (86%) participants during the educational movie and in 9 (43%) during the horror movie.
However, the researchers found no effect of either movie on thrombin-antithrombin complexes, D-dimer, or prothrombin fragments 1+2. They said this suggests that although acute fear may trigger coagulation, it does not lead to actual clot formation.
The team pointed out some study limitations but concluded that, in young and healthy adults, “watching blood-curdling movies is associated with an increase in blood coagulant factor VIII without actual thrombin formation.”
The researchers believe this phenomenon may confer an important evolutionary benefit by preparing the body for blood loss during life-threatening situations.
A potential target for IDH1-mutant cancers
acute myeloid leukemia
Researchers say they have identified a potential therapeutic target for IDH1-mutant malignancies.
Preclinical experiments showed that tumors characterized by IDH1 mutations are “extremely vulnerable” to depletion of NAD+, a metabolic cofactor.
“Our finding . . . supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers,” said Daniel Cahill, MD, PhD, of Massachusetts General Hospital in Boston.
Dr Cahill and his colleagues described their research in Cancer Cell.
IDH1 and IDH2 are known to play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into ATP, providing the energy needed for cellular survival.
In 2008, researchers discovered that IDH1 mutations are involved in several cancers. The gene is mutated in around 20% of adult gliomas, in more than 10% of acute myeloid leukemias, and in a smaller percentage of other cancers.
One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development. Drugs that decrease levels of 2-HG are currently under development.
Dr Cahill and his colleagues wanted to find additional ways of blocking the mutation’s effects, so they inhibited mutant IDH1 in tumor cells. They were surprised to find that this reduced 2-HG levels, but, in many cases, that reduction did not halt cell growth.
Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes.
Additional experiments showed that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.
“Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors,” said Hiroaki Wakimoto, MD, PhD, of Massachusetts General Hospital.
“In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation.”
acute myeloid leukemia
Researchers say they have identified a potential therapeutic target for IDH1-mutant malignancies.
Preclinical experiments showed that tumors characterized by IDH1 mutations are “extremely vulnerable” to depletion of NAD+, a metabolic cofactor.
“Our finding . . . supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers,” said Daniel Cahill, MD, PhD, of Massachusetts General Hospital in Boston.
Dr Cahill and his colleagues described their research in Cancer Cell.
IDH1 and IDH2 are known to play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into ATP, providing the energy needed for cellular survival.
In 2008, researchers discovered that IDH1 mutations are involved in several cancers. The gene is mutated in around 20% of adult gliomas, in more than 10% of acute myeloid leukemias, and in a smaller percentage of other cancers.
One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development. Drugs that decrease levels of 2-HG are currently under development.
Dr Cahill and his colleagues wanted to find additional ways of blocking the mutation’s effects, so they inhibited mutant IDH1 in tumor cells. They were surprised to find that this reduced 2-HG levels, but, in many cases, that reduction did not halt cell growth.
Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes.
Additional experiments showed that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.
“Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors,” said Hiroaki Wakimoto, MD, PhD, of Massachusetts General Hospital.
“In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation.”
acute myeloid leukemia
Researchers say they have identified a potential therapeutic target for IDH1-mutant malignancies.
Preclinical experiments showed that tumors characterized by IDH1 mutations are “extremely vulnerable” to depletion of NAD+, a metabolic cofactor.
“Our finding . . . supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers,” said Daniel Cahill, MD, PhD, of Massachusetts General Hospital in Boston.
Dr Cahill and his colleagues described their research in Cancer Cell.
IDH1 and IDH2 are known to play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into ATP, providing the energy needed for cellular survival.
In 2008, researchers discovered that IDH1 mutations are involved in several cancers. The gene is mutated in around 20% of adult gliomas, in more than 10% of acute myeloid leukemias, and in a smaller percentage of other cancers.
One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development. Drugs that decrease levels of 2-HG are currently under development.
Dr Cahill and his colleagues wanted to find additional ways of blocking the mutation’s effects, so they inhibited mutant IDH1 in tumor cells. They were surprised to find that this reduced 2-HG levels, but, in many cases, that reduction did not halt cell growth.
Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes.
Additional experiments showed that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.
“Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors,” said Hiroaki Wakimoto, MD, PhD, of Massachusetts General Hospital.
“In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation.”
Antiplatelet agent shows promise in phase 1 trial
Image by Andre E.X. Brown
Results of a phase 1 study suggest the experimental agent PZ-128 provides rapid and reversible inhibition of platelet aggregation.
PZ-128 inhibited platelet aggregation in a cohort of patients who had vascular disease or multiple risk factors for coronary artery disease.
This effect was dose-dependent and diminished over time. The drug did not affect bleeding, coagulation, clinical chemistry, or ECG parameters.
Investigators reported these results in Arteriosclerosis, Thrombosis and Vascular Biology.
The team explained that PZ-128 is a protease-activated receptor-1 (PAR1)-based pepducin intended as an antiplatelet agent. Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor.
The current study is the first demonstration of pepducins’ potential benefits in humans, said study author Athan Kuliopulos, MD, PhD, of Tufts Medical Center in Boston, Massachusetts.
He and his colleagues tested PZ-128 in 31 patients, ages 43 to 74. The patients had vascular disease (22%)—coronary artery disease, previous myocardial infarction, etc.—or multiple coronary artery disease risk factors—dyslipidemia (81%), hypertension (69%), diabetes (34%), etc.
Many of the patients were taking other medications at baseline, including blood pressure medications (66%), aspirin (63%), lipid-lowering medications (56%), and diabetes medications (22%).
The patients received PZ-128 by 1- to 2-hour-long intravenous infusion at doses ranging from 0.01 mg/kg to 2 mg/kg. The investigators evaluated patients at baseline and 0.5, 1, 2, 6, and 24 hours after dosing, as well as 7 to 10 days after dosing.
PZ-128 had a dose-dependent inhibitory effect on platelet aggregation stimulated by the PAR1 agonist SFLLRN (8 µmol/L). At 30 minutes to 6 hours after dosing, the investigators observed 20% to 40% inhibition with PZ-128 at 0.3 mg/kg, 40% to 60% inhibition at 0.5 mg/kg, and 80% to 100% inhibition at 1 to 2 mg/kg.
Patients who were receiving aspirin in the 0.5 mg/kg and 1 mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours after dosing and 95% to 100% inhibition by 6 hours.
The impact of PZ-128 was reversible, with 50% recovery of aggregation to SFLLRN by 24 hours and near-complete recovery by 192 hours.
The investigators said PZ-128 did not have any significant effects on aggregation induced by AYPGKF, ADP, or collagen, which suggests the observed effects were specific to PAR1.
Likewise, the team said PZ-128 did not have any significant effects on bleeding, coagulation, clinical chemistry, or ECG parameters.
The investigators noted that there are currently no drugs on the market that target PAR1 and can be used during procedures when the risk of serious complications is high.
The PAR1 inhibitor vorapaxar is available for non-acute use in patients with a prior myocardial infarction or current peripheral artery disease. But the drug, whose effects build slowly and are long-lasting, was not approved for use during cardiac procedures due to a risk of excessive bleeding, Dr Kuliopulos said.
By contrast, PZ-128 appears able to block PAR1 fast enough to be used in an urgent procedure and for a time short enough to limit bleeding risk afterward, he said. Of course, more research is needed to confirm this.
To that end, the investigators are planning a phase 2 study of PZ-128 in up to 600 patients who have acute coronary syndromes or are undergoing percutaneous coronary intervention.
Image by Andre E.X. Brown
Results of a phase 1 study suggest the experimental agent PZ-128 provides rapid and reversible inhibition of platelet aggregation.
PZ-128 inhibited platelet aggregation in a cohort of patients who had vascular disease or multiple risk factors for coronary artery disease.
This effect was dose-dependent and diminished over time. The drug did not affect bleeding, coagulation, clinical chemistry, or ECG parameters.
Investigators reported these results in Arteriosclerosis, Thrombosis and Vascular Biology.
The team explained that PZ-128 is a protease-activated receptor-1 (PAR1)-based pepducin intended as an antiplatelet agent. Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor.
The current study is the first demonstration of pepducins’ potential benefits in humans, said study author Athan Kuliopulos, MD, PhD, of Tufts Medical Center in Boston, Massachusetts.
He and his colleagues tested PZ-128 in 31 patients, ages 43 to 74. The patients had vascular disease (22%)—coronary artery disease, previous myocardial infarction, etc.—or multiple coronary artery disease risk factors—dyslipidemia (81%), hypertension (69%), diabetes (34%), etc.
Many of the patients were taking other medications at baseline, including blood pressure medications (66%), aspirin (63%), lipid-lowering medications (56%), and diabetes medications (22%).
The patients received PZ-128 by 1- to 2-hour-long intravenous infusion at doses ranging from 0.01 mg/kg to 2 mg/kg. The investigators evaluated patients at baseline and 0.5, 1, 2, 6, and 24 hours after dosing, as well as 7 to 10 days after dosing.
PZ-128 had a dose-dependent inhibitory effect on platelet aggregation stimulated by the PAR1 agonist SFLLRN (8 µmol/L). At 30 minutes to 6 hours after dosing, the investigators observed 20% to 40% inhibition with PZ-128 at 0.3 mg/kg, 40% to 60% inhibition at 0.5 mg/kg, and 80% to 100% inhibition at 1 to 2 mg/kg.
Patients who were receiving aspirin in the 0.5 mg/kg and 1 mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours after dosing and 95% to 100% inhibition by 6 hours.
The impact of PZ-128 was reversible, with 50% recovery of aggregation to SFLLRN by 24 hours and near-complete recovery by 192 hours.
The investigators said PZ-128 did not have any significant effects on aggregation induced by AYPGKF, ADP, or collagen, which suggests the observed effects were specific to PAR1.
Likewise, the team said PZ-128 did not have any significant effects on bleeding, coagulation, clinical chemistry, or ECG parameters.
The investigators noted that there are currently no drugs on the market that target PAR1 and can be used during procedures when the risk of serious complications is high.
The PAR1 inhibitor vorapaxar is available for non-acute use in patients with a prior myocardial infarction or current peripheral artery disease. But the drug, whose effects build slowly and are long-lasting, was not approved for use during cardiac procedures due to a risk of excessive bleeding, Dr Kuliopulos said.
By contrast, PZ-128 appears able to block PAR1 fast enough to be used in an urgent procedure and for a time short enough to limit bleeding risk afterward, he said. Of course, more research is needed to confirm this.
To that end, the investigators are planning a phase 2 study of PZ-128 in up to 600 patients who have acute coronary syndromes or are undergoing percutaneous coronary intervention.
Image by Andre E.X. Brown
Results of a phase 1 study suggest the experimental agent PZ-128 provides rapid and reversible inhibition of platelet aggregation.
PZ-128 inhibited platelet aggregation in a cohort of patients who had vascular disease or multiple risk factors for coronary artery disease.
This effect was dose-dependent and diminished over time. The drug did not affect bleeding, coagulation, clinical chemistry, or ECG parameters.
Investigators reported these results in Arteriosclerosis, Thrombosis and Vascular Biology.
The team explained that PZ-128 is a protease-activated receptor-1 (PAR1)-based pepducin intended as an antiplatelet agent. Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor.
The current study is the first demonstration of pepducins’ potential benefits in humans, said study author Athan Kuliopulos, MD, PhD, of Tufts Medical Center in Boston, Massachusetts.
He and his colleagues tested PZ-128 in 31 patients, ages 43 to 74. The patients had vascular disease (22%)—coronary artery disease, previous myocardial infarction, etc.—or multiple coronary artery disease risk factors—dyslipidemia (81%), hypertension (69%), diabetes (34%), etc.
Many of the patients were taking other medications at baseline, including blood pressure medications (66%), aspirin (63%), lipid-lowering medications (56%), and diabetes medications (22%).
The patients received PZ-128 by 1- to 2-hour-long intravenous infusion at doses ranging from 0.01 mg/kg to 2 mg/kg. The investigators evaluated patients at baseline and 0.5, 1, 2, 6, and 24 hours after dosing, as well as 7 to 10 days after dosing.
PZ-128 had a dose-dependent inhibitory effect on platelet aggregation stimulated by the PAR1 agonist SFLLRN (8 µmol/L). At 30 minutes to 6 hours after dosing, the investigators observed 20% to 40% inhibition with PZ-128 at 0.3 mg/kg, 40% to 60% inhibition at 0.5 mg/kg, and 80% to 100% inhibition at 1 to 2 mg/kg.
Patients who were receiving aspirin in the 0.5 mg/kg and 1 mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours after dosing and 95% to 100% inhibition by 6 hours.
The impact of PZ-128 was reversible, with 50% recovery of aggregation to SFLLRN by 24 hours and near-complete recovery by 192 hours.
The investigators said PZ-128 did not have any significant effects on aggregation induced by AYPGKF, ADP, or collagen, which suggests the observed effects were specific to PAR1.
Likewise, the team said PZ-128 did not have any significant effects on bleeding, coagulation, clinical chemistry, or ECG parameters.
The investigators noted that there are currently no drugs on the market that target PAR1 and can be used during procedures when the risk of serious complications is high.
The PAR1 inhibitor vorapaxar is available for non-acute use in patients with a prior myocardial infarction or current peripheral artery disease. But the drug, whose effects build slowly and are long-lasting, was not approved for use during cardiac procedures due to a risk of excessive bleeding, Dr Kuliopulos said.
By contrast, PZ-128 appears able to block PAR1 fast enough to be used in an urgent procedure and for a time short enough to limit bleeding risk afterward, he said. Of course, more research is needed to confirm this.
To that end, the investigators are planning a phase 2 study of PZ-128 in up to 600 patients who have acute coronary syndromes or are undergoing percutaneous coronary intervention.
ASH: First shot across the bow for CAR T cells in multiple myeloma
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.
CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.
“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.
The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.
While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.
Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.
The 12 patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 106 to 9 x 106 T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.
“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”
The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.
CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.
“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.
The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.
While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.
Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.
The 12 patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 106 to 9 x 106 T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.
“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”
The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.
CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.
“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.
The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.
While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.
Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.
The 12 patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 106 to 9 x 106 T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.
“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”
The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2015
Key clinical point: The first clinical trial of a CAR targeting BCMA demonstrated strong antimyeloma activity in patients with at least 3 prior lines of myeloma therapy.
Major finding: Myeloma in plasma cells was reduced from 90% to 0% in one patient.
Data source: Phase I study in 12 patients with at least 3 prior lines of multiple myeloma therapy.
Disclosures: Dr. Kochenderfer reported consultancy with Bluebird Bio and off-label use of cyclophosphamide and fludarabine.
Anti-BCL2, CD20 combo safe, effective in untreated CLL
ORLANDO – An experimental combination of obinutuzumab and venetoclax appears safe as frontline therapy for patients with active, untreated chronic lymphocytic leukemia and comorbidities.
In the safety run-in portion of a phase 3, open-label trial comparing the combination of obinutuzumab (Gazyva) and the investigational Bcl-2 inhibitor venetoclax with obinutuzumab and its usual partner chlorambucil in 12 patients, only two of seven patients classified as being at high risk for the tumor lysis syndrome (TLS) developed laboratory-defined TLS, and no patients had clinical TLS.
The combination did not meet any of the pre-specified stopping criteria, and early data hinted at efficacy for the combination, said Dr. Kirsten Fischer, from the Center for Integrated Oncology at University Hospital Cologne in Germany.
“As with previous reports, our data confirm rapid and profound reduction in lymphocyte counts after the first dose obinutuzumab in all 12 [evaluable] patients,” she said at the American Society of Hematology annual meeting.
In the CLL 11 trial, investigators in the German CLL group previously showed that the combination of the anti-CD20 antibody obinutuzumab and chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. The combination is approved in the United States for adults with treatment-naïve CLL.
Venetoclax has been shown to have good efficacy against relapsed/refractory CLL both as monotherapy and in combination with rituximab, prompting the investigators to explore it in combination with the rituximab follow-on drug obinutuzumab.
In the safety run-in phase of the CLL 14 trial, the investigators enrolled 13 adults (median age 75, range 59-88 years) with newly diagnosed, active confirmed CLL and coexisting medical conditions as determined either by a score greater 6 on the cumulative illness rating scale (CIRS) or by estimated creatinine clearance less than 70 mL/min.
The patients were treated with 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously 100 mg on day 1 and 900 mg on day 2, with the option to deliver 1,000 mg on day 1 instead, then 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 for cycles 2-6.
The dose of venetoclax was titrated upward gradually, with doses of 20 mg, 50 mg, 100 mg, 200 mg, and up to 400 mg administered starting on day 22 of cycle 1.
Planned stopping criteria were one treatment-related death or a grade 4 adverse event related to clinical TLS despite prophylaxis as specified by the protocol.
At the time of data cutoff (October 2015), 12 patients had been on treatment for at least 4 weeks and had reached the maximum venetoclax dose. Two patients had reached 11 cycles, three had reached 10 cycles, and seven had reached 8 cycles.
Grade 1 or 2 adverse events in all 13 enrolled patients included infusion-related reactions in 8; infections in 6; diarrhea, hyperkalemia, and constipation in 5; nausea, dizziness and cough in 4; and fatigue, headache and pruritus in 3.
Grade 3 or 4 adverse events were neutropenia in five patients; infusion related reactions; syncope, thrombocytopenia and laboratory-defined TLS in two patients; and bradycardia, hyperglycemia, influenza, leucopenia, pyrexia, respiratory tract infection, and elevated transaminases in one patient each.
As noted, all 12 evaluable patients had rapid drops in absolute lymphocyte counts, and all but one had complete resolution of lymphadenopathy after three cycles, with the improvement maintained after six cycles. The remaining patient had a decrease to near normal after both three and six cycles.
Of the 12 patients, 11 had a partial response after three cycles, and the remaining patient had stable disease, for an overall response rate of 92%. The overall response rate after six cycles was 100%, with all patients having a partial response.
The data were sufficiently good to justify continuing with the randomized phase, which began in August 2015, Dr. Fischer noted.
The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.
ORLANDO – An experimental combination of obinutuzumab and venetoclax appears safe as frontline therapy for patients with active, untreated chronic lymphocytic leukemia and comorbidities.
In the safety run-in portion of a phase 3, open-label trial comparing the combination of obinutuzumab (Gazyva) and the investigational Bcl-2 inhibitor venetoclax with obinutuzumab and its usual partner chlorambucil in 12 patients, only two of seven patients classified as being at high risk for the tumor lysis syndrome (TLS) developed laboratory-defined TLS, and no patients had clinical TLS.
The combination did not meet any of the pre-specified stopping criteria, and early data hinted at efficacy for the combination, said Dr. Kirsten Fischer, from the Center for Integrated Oncology at University Hospital Cologne in Germany.
“As with previous reports, our data confirm rapid and profound reduction in lymphocyte counts after the first dose obinutuzumab in all 12 [evaluable] patients,” she said at the American Society of Hematology annual meeting.
In the CLL 11 trial, investigators in the German CLL group previously showed that the combination of the anti-CD20 antibody obinutuzumab and chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. The combination is approved in the United States for adults with treatment-naïve CLL.
Venetoclax has been shown to have good efficacy against relapsed/refractory CLL both as monotherapy and in combination with rituximab, prompting the investigators to explore it in combination with the rituximab follow-on drug obinutuzumab.
In the safety run-in phase of the CLL 14 trial, the investigators enrolled 13 adults (median age 75, range 59-88 years) with newly diagnosed, active confirmed CLL and coexisting medical conditions as determined either by a score greater 6 on the cumulative illness rating scale (CIRS) or by estimated creatinine clearance less than 70 mL/min.
The patients were treated with 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously 100 mg on day 1 and 900 mg on day 2, with the option to deliver 1,000 mg on day 1 instead, then 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 for cycles 2-6.
The dose of venetoclax was titrated upward gradually, with doses of 20 mg, 50 mg, 100 mg, 200 mg, and up to 400 mg administered starting on day 22 of cycle 1.
Planned stopping criteria were one treatment-related death or a grade 4 adverse event related to clinical TLS despite prophylaxis as specified by the protocol.
At the time of data cutoff (October 2015), 12 patients had been on treatment for at least 4 weeks and had reached the maximum venetoclax dose. Two patients had reached 11 cycles, three had reached 10 cycles, and seven had reached 8 cycles.
Grade 1 or 2 adverse events in all 13 enrolled patients included infusion-related reactions in 8; infections in 6; diarrhea, hyperkalemia, and constipation in 5; nausea, dizziness and cough in 4; and fatigue, headache and pruritus in 3.
Grade 3 or 4 adverse events were neutropenia in five patients; infusion related reactions; syncope, thrombocytopenia and laboratory-defined TLS in two patients; and bradycardia, hyperglycemia, influenza, leucopenia, pyrexia, respiratory tract infection, and elevated transaminases in one patient each.
As noted, all 12 evaluable patients had rapid drops in absolute lymphocyte counts, and all but one had complete resolution of lymphadenopathy after three cycles, with the improvement maintained after six cycles. The remaining patient had a decrease to near normal after both three and six cycles.
Of the 12 patients, 11 had a partial response after three cycles, and the remaining patient had stable disease, for an overall response rate of 92%. The overall response rate after six cycles was 100%, with all patients having a partial response.
The data were sufficiently good to justify continuing with the randomized phase, which began in August 2015, Dr. Fischer noted.
The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.
ORLANDO – An experimental combination of obinutuzumab and venetoclax appears safe as frontline therapy for patients with active, untreated chronic lymphocytic leukemia and comorbidities.
In the safety run-in portion of a phase 3, open-label trial comparing the combination of obinutuzumab (Gazyva) and the investigational Bcl-2 inhibitor venetoclax with obinutuzumab and its usual partner chlorambucil in 12 patients, only two of seven patients classified as being at high risk for the tumor lysis syndrome (TLS) developed laboratory-defined TLS, and no patients had clinical TLS.
The combination did not meet any of the pre-specified stopping criteria, and early data hinted at efficacy for the combination, said Dr. Kirsten Fischer, from the Center for Integrated Oncology at University Hospital Cologne in Germany.
“As with previous reports, our data confirm rapid and profound reduction in lymphocyte counts after the first dose obinutuzumab in all 12 [evaluable] patients,” she said at the American Society of Hematology annual meeting.
In the CLL 11 trial, investigators in the German CLL group previously showed that the combination of the anti-CD20 antibody obinutuzumab and chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. The combination is approved in the United States for adults with treatment-naïve CLL.
Venetoclax has been shown to have good efficacy against relapsed/refractory CLL both as monotherapy and in combination with rituximab, prompting the investigators to explore it in combination with the rituximab follow-on drug obinutuzumab.
In the safety run-in phase of the CLL 14 trial, the investigators enrolled 13 adults (median age 75, range 59-88 years) with newly diagnosed, active confirmed CLL and coexisting medical conditions as determined either by a score greater 6 on the cumulative illness rating scale (CIRS) or by estimated creatinine clearance less than 70 mL/min.
The patients were treated with 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously 100 mg on day 1 and 900 mg on day 2, with the option to deliver 1,000 mg on day 1 instead, then 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 for cycles 2-6.
The dose of venetoclax was titrated upward gradually, with doses of 20 mg, 50 mg, 100 mg, 200 mg, and up to 400 mg administered starting on day 22 of cycle 1.
Planned stopping criteria were one treatment-related death or a grade 4 adverse event related to clinical TLS despite prophylaxis as specified by the protocol.
At the time of data cutoff (October 2015), 12 patients had been on treatment for at least 4 weeks and had reached the maximum venetoclax dose. Two patients had reached 11 cycles, three had reached 10 cycles, and seven had reached 8 cycles.
Grade 1 or 2 adverse events in all 13 enrolled patients included infusion-related reactions in 8; infections in 6; diarrhea, hyperkalemia, and constipation in 5; nausea, dizziness and cough in 4; and fatigue, headache and pruritus in 3.
Grade 3 or 4 adverse events were neutropenia in five patients; infusion related reactions; syncope, thrombocytopenia and laboratory-defined TLS in two patients; and bradycardia, hyperglycemia, influenza, leucopenia, pyrexia, respiratory tract infection, and elevated transaminases in one patient each.
As noted, all 12 evaluable patients had rapid drops in absolute lymphocyte counts, and all but one had complete resolution of lymphadenopathy after three cycles, with the improvement maintained after six cycles. The remaining patient had a decrease to near normal after both three and six cycles.
Of the 12 patients, 11 had a partial response after three cycles, and the remaining patient had stable disease, for an overall response rate of 92%. The overall response rate after six cycles was 100%, with all patients having a partial response.
The data were sufficiently good to justify continuing with the randomized phase, which began in August 2015, Dr. Fischer noted.
The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.
AT ASH 2015
Key clinical point: Patients with CLL and comorbidities were able to tolerate an experimental regimen of obinutuzumab and venetoclax.
Major finding: Two of 12 evaluable patients had evidence of laboratory-defined but not clinical tumor lysis syndrome.
Data source: Safety run-in phase of a randomized phase 3 trial with 13 patients with chronic lymphocytic leukemia and comorbidities.
Disclosures: The study is sponsored by Hoffman-La Roche and AbbVie. Dr. Fischer disclosed receiving travel grants from Hoffman-La Roche.
Bystander CPR rising in children with cardiac arrest
ORLANDO – Bystander CPR was provided in 49% of U.S. cases of pediatric out-of-hospital cardiac arrest during 2013-2014, a major improvement over the 35% rate in a prior study 15 years ago, Dr. Maryam Y. Naim reported at the American Heart Association scientific sessions.
She presented an analysis of 2,176 out-of-hospital cardiac arrests (OHCA) in patients up to age 18 years who were included in the Cardiac Arrest Registry to Enhance Survival (CARES), the nation’s largest OHCA registry. Patients with traumatic OHCA and those whose bystander CPR (BCPR) was provided by a health care professional weren’t included.
Overall, the rate of neurologically favorable survival in pediatric recipients of BCPR was 11%, compared with 7% when BCPR wasn’t provided. But the results were far more impressive in the 14% of cardiac arrests that occurred outside the home, where the rate of neurologically favorable survival in BCPR recipients was 34%, more than twice the 15% figure for nonrecipients, according to Dr. Naim, a pediatrician and cardiac intensivist at Children’s Hospital of Philadelphia and the University of Pennsylvania.
Infants accounted for 47% of all pediatric OHCA, and in these youngest patients BCPR was of no benefit.
“The most common etiology of cardiac arrest in infants is sudden infant death syndrome. These are children who are found unresponsive in their cribs, and sometimes they’ve been dead a long time. We need to find something different for this population: perhaps developing a monitor to signal when an infant stops breathing or the heart rate goes down,” she said.
The fact that the BCPR rate in pediatric OHCA has climbed to 49% speaks well for public health efforts to improve education and awareness. Of those who received BCPR during 2013 and 2014, half got compression-only CPR, suggesting increasing adherence to the 2010 AHA guidelines for CPR and emergency cardiovascular care, which emphasized compression-only CPR as a viable alternative to conventional CPR, Dr. Naim added.
Her study highlighted a racial disparity in the application of BCPR in children and adolescents: Sixty percent of white youths with OHCA received BCPR, compared with 42% of blacks and 48% of Hispanics.
“About 70% of all bystander CPR was provided by a family member at home. So there’s really an opportunity there, especially in minority communities, to further increase education and awareness about bystander CPR, teaching family members to do it and also how to call 911 to start the chain of response,” she said.
Dr. Naim reported having no financial conflicts regarding her study.
ORLANDO – Bystander CPR was provided in 49% of U.S. cases of pediatric out-of-hospital cardiac arrest during 2013-2014, a major improvement over the 35% rate in a prior study 15 years ago, Dr. Maryam Y. Naim reported at the American Heart Association scientific sessions.
She presented an analysis of 2,176 out-of-hospital cardiac arrests (OHCA) in patients up to age 18 years who were included in the Cardiac Arrest Registry to Enhance Survival (CARES), the nation’s largest OHCA registry. Patients with traumatic OHCA and those whose bystander CPR (BCPR) was provided by a health care professional weren’t included.
Overall, the rate of neurologically favorable survival in pediatric recipients of BCPR was 11%, compared with 7% when BCPR wasn’t provided. But the results were far more impressive in the 14% of cardiac arrests that occurred outside the home, where the rate of neurologically favorable survival in BCPR recipients was 34%, more than twice the 15% figure for nonrecipients, according to Dr. Naim, a pediatrician and cardiac intensivist at Children’s Hospital of Philadelphia and the University of Pennsylvania.
Infants accounted for 47% of all pediatric OHCA, and in these youngest patients BCPR was of no benefit.
“The most common etiology of cardiac arrest in infants is sudden infant death syndrome. These are children who are found unresponsive in their cribs, and sometimes they’ve been dead a long time. We need to find something different for this population: perhaps developing a monitor to signal when an infant stops breathing or the heart rate goes down,” she said.
The fact that the BCPR rate in pediatric OHCA has climbed to 49% speaks well for public health efforts to improve education and awareness. Of those who received BCPR during 2013 and 2014, half got compression-only CPR, suggesting increasing adherence to the 2010 AHA guidelines for CPR and emergency cardiovascular care, which emphasized compression-only CPR as a viable alternative to conventional CPR, Dr. Naim added.
Her study highlighted a racial disparity in the application of BCPR in children and adolescents: Sixty percent of white youths with OHCA received BCPR, compared with 42% of blacks and 48% of Hispanics.
“About 70% of all bystander CPR was provided by a family member at home. So there’s really an opportunity there, especially in minority communities, to further increase education and awareness about bystander CPR, teaching family members to do it and also how to call 911 to start the chain of response,” she said.
Dr. Naim reported having no financial conflicts regarding her study.
ORLANDO – Bystander CPR was provided in 49% of U.S. cases of pediatric out-of-hospital cardiac arrest during 2013-2014, a major improvement over the 35% rate in a prior study 15 years ago, Dr. Maryam Y. Naim reported at the American Heart Association scientific sessions.
She presented an analysis of 2,176 out-of-hospital cardiac arrests (OHCA) in patients up to age 18 years who were included in the Cardiac Arrest Registry to Enhance Survival (CARES), the nation’s largest OHCA registry. Patients with traumatic OHCA and those whose bystander CPR (BCPR) was provided by a health care professional weren’t included.
Overall, the rate of neurologically favorable survival in pediatric recipients of BCPR was 11%, compared with 7% when BCPR wasn’t provided. But the results were far more impressive in the 14% of cardiac arrests that occurred outside the home, where the rate of neurologically favorable survival in BCPR recipients was 34%, more than twice the 15% figure for nonrecipients, according to Dr. Naim, a pediatrician and cardiac intensivist at Children’s Hospital of Philadelphia and the University of Pennsylvania.
Infants accounted for 47% of all pediatric OHCA, and in these youngest patients BCPR was of no benefit.
“The most common etiology of cardiac arrest in infants is sudden infant death syndrome. These are children who are found unresponsive in their cribs, and sometimes they’ve been dead a long time. We need to find something different for this population: perhaps developing a monitor to signal when an infant stops breathing or the heart rate goes down,” she said.
The fact that the BCPR rate in pediatric OHCA has climbed to 49% speaks well for public health efforts to improve education and awareness. Of those who received BCPR during 2013 and 2014, half got compression-only CPR, suggesting increasing adherence to the 2010 AHA guidelines for CPR and emergency cardiovascular care, which emphasized compression-only CPR as a viable alternative to conventional CPR, Dr. Naim added.
Her study highlighted a racial disparity in the application of BCPR in children and adolescents: Sixty percent of white youths with OHCA received BCPR, compared with 42% of blacks and 48% of Hispanics.
“About 70% of all bystander CPR was provided by a family member at home. So there’s really an opportunity there, especially in minority communities, to further increase education and awareness about bystander CPR, teaching family members to do it and also how to call 911 to start the chain of response,” she said.
Dr. Naim reported having no financial conflicts regarding her study.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Nearly half of all children and adolescents with out-of-hospital cardiac arrest in 2013-2014 got bystander CPR.
Major finding: The rate of neurologically favorable survival in pediatric patients with out-of-hospital cardiac arrest who receive bystander CPR is 34%, compared with 15% in those who don’t get the intervention.
Data source: An analysis of 2,176 out-of-hospital cardiac arrests in the Cardiac Arrest Registry to Enhance Survival during 2013 and 2014.
Disclosures: The presenter reported having no financial conflicts regarding her study.
