A common clinical challenge encountered by vascular surgeons – what to do with asymptomatic carotid artery disease – will be a main focus of the Tuesday afternoon session, “New Key Developments in the Management of Patients with Carotid Disease.”

“Overall, this session will be a look at mostly asymptomatic carotid stenosis, also with some presentations from experts in the field on how to interpret the long-term results of all these trials and incorporate them into your clinical practice. There should be a lot of excitement about this session in light of recent CMS decisions to reimburse for asymptomatic carotid stenosis” in patients who are at high risk for surgery. “That’s a big leap forward,” said moderator Dr. L. Nelson Hopkins of the State University of New York, Buffalo.

Session 5:
New Key Developments in the Management of Patients with Carotid Disease
Tuesday,1:00 p.m –2:42 p.m.

Grand Ballroom East, 3rd Floor

A common clinical challenge encountered by vascular surgeons – what to do with asymptomatic carotid artery disease – will be a main focus of the Tuesday afternoon session, “New Key Developments in the Management of Patients with Carotid Disease.”

“Overall, this session will be a look at mostly asymptomatic carotid stenosis, also with some presentations from experts in the field on how to interpret the long-term results of all these trials and incorporate them into your clinical practice. There should be a lot of excitement about this session in light of recent CMS decisions to reimburse for asymptomatic carotid stenosis” in patients who are at high risk for surgery. “That’s a big leap forward,” said moderator Dr. L. Nelson Hopkins of the State University of New York, Buffalo.

Session 5:
New Key Developments in the Management of Patients with Carotid Disease
Tuesday,1:00 p.m –2:42 p.m.

Grand Ballroom East, 3rd Floor

A common clinical challenge encountered by vascular surgeons – what to do with asymptomatic carotid artery disease – will be a main focus of the Tuesday afternoon session, “New Key Developments in the Management of Patients with Carotid Disease.”

“Overall, this session will be a look at mostly asymptomatic carotid stenosis, also with some presentations from experts in the field on how to interpret the long-term results of all these trials and incorporate them into your clinical practice. There should be a lot of excitement about this session in light of recent CMS decisions to reimburse for asymptomatic carotid stenosis” in patients who are at high risk for surgery. “That’s a big leap forward,” said moderator Dr. L. Nelson Hopkins of the State University of New York, Buffalo.

Session 5:
New Key Developments in the Management of Patients with Carotid Disease
Tuesday,1:00 p.m –2:42 p.m.

Grand Ballroom East, 3rd Floor

Neither time of day, nor number of procedures performed by the clinician impacted adenoma detection rates in a large community-based setting, a study has shown.

Previously, mixed and scanty data on whether endoscopist fatigue correlates with colonoscopy quality in a community-based setting – where the majority of colonoscopies are performed – brought into question the link between a clinician’s detection rates and patient mortality rates due to interval cancers. Colorectal cancer is the second leading cause of cancer death in the U.S.

The most recent recommended adenoma detection rates – considered benchmarks of colonoscopic quality – are at or above 20% in men and at or above 30% in women, according to the American College of Gastroenterology.

A new study published online in Gastrointestinal Endoscopy, however, indicates that the endoscopists working in a large, integrated, community-based health care system exceeded those quality benchmarks.

Gastroenterologist Alexander T. Lee, MD, and his colleagues identified 126 gastroenterologists in the health system, Kaiser Permanente Northern California, who performed an average of six endoscopy procedures per day – 259,064 in all – between 2010 and 2013, including 76,445 screenings and surveillance colonoscopies. They found that per physician, adenoma detection rates for screening colonoscopy examinations averaged 28.9% and 45.4% for surveillance examinations. By patient gender, the average detection rates per screening were 34.8% for men and 24.0% for women; detection rates per surveillance, the rates were 51.1% for men and 37.8% for women.

After adjusting for confounders, the investigators analyzed each physician’s average adenoma detection rates in association with the time of day each GI procedure was performed, the number of GI procedures performed before each colonoscopy, and the level of complexity of any prior procedures performed at the time of the screening or surveillance colonoscopy. Dr. Lee and his coinvestigators also found that compared with morning examinations, afternoon colonoscopies were not associated with lower adenoma detection for screening examinations, surveillance examinations, or their combination (odds ratio for combination, 0.99; 95% confidence interval, 0.96-1.03). Additionally, neither the number of procedures performed before a given colonoscopy, nor a prior procedure’s complexity, was inversely associated with adenoma detection (OR for detection rates late in the day vs. first procedure of the day, 0.99; 95% CI, 0.94-1.04).

In systems where physicians have larger daily GI procedure loads, there could be an adverse impact on adenoma detection rates, wrote Dr. Lee and his coauthors, but they also noted that quality could similarly be diluted by a lower ratio of procedures to clinician, as well. Whether other demands on a physician’s time, such as other clinical procedures or office tasks, might adversely impact detection rates, Dr. Lee and his colleagues didn’t know because they measured only the colonoscopic screening and surveillance activities. “The reported lack of an association with time of day would argue against this being a substantial factor in [this] study,” they wrote.

“The fact that increased adenoma detection was found only for screening colonoscopy examinations raises the question of whether endoscopists were systematically more vigilant during screening procedures, although the higher observed adenoma detection rates for surveillance examinations suggest otherwise,” the investigators wrote.

None of the investigators listed had any relevant disclosures.
 

[email protected]

On Twitter @whitneymcknight

Neither time of day, nor number of procedures performed by the clinician impacted adenoma detection rates in a large community-based setting, a study has shown.

Previously, mixed and scanty data on whether endoscopist fatigue correlates with colonoscopy quality in a community-based setting – where the majority of colonoscopies are performed – brought into question the link between a clinician’s detection rates and patient mortality rates due to interval cancers. Colorectal cancer is the second leading cause of cancer death in the U.S.

The most recent recommended adenoma detection rates – considered benchmarks of colonoscopic quality – are at or above 20% in men and at or above 30% in women, according to the American College of Gastroenterology.

A new study published online in Gastrointestinal Endoscopy, however, indicates that the endoscopists working in a large, integrated, community-based health care system exceeded those quality benchmarks.

Gastroenterologist Alexander T. Lee, MD, and his colleagues identified 126 gastroenterologists in the health system, Kaiser Permanente Northern California, who performed an average of six endoscopy procedures per day – 259,064 in all – between 2010 and 2013, including 76,445 screenings and surveillance colonoscopies. They found that per physician, adenoma detection rates for screening colonoscopy examinations averaged 28.9% and 45.4% for surveillance examinations. By patient gender, the average detection rates per screening were 34.8% for men and 24.0% for women; detection rates per surveillance, the rates were 51.1% for men and 37.8% for women.

After adjusting for confounders, the investigators analyzed each physician’s average adenoma detection rates in association with the time of day each GI procedure was performed, the number of GI procedures performed before each colonoscopy, and the level of complexity of any prior procedures performed at the time of the screening or surveillance colonoscopy. Dr. Lee and his coinvestigators also found that compared with morning examinations, afternoon colonoscopies were not associated with lower adenoma detection for screening examinations, surveillance examinations, or their combination (odds ratio for combination, 0.99; 95% confidence interval, 0.96-1.03). Additionally, neither the number of procedures performed before a given colonoscopy, nor a prior procedure’s complexity, was inversely associated with adenoma detection (OR for detection rates late in the day vs. first procedure of the day, 0.99; 95% CI, 0.94-1.04).

In systems where physicians have larger daily GI procedure loads, there could be an adverse impact on adenoma detection rates, wrote Dr. Lee and his coauthors, but they also noted that quality could similarly be diluted by a lower ratio of procedures to clinician, as well. Whether other demands on a physician’s time, such as other clinical procedures or office tasks, might adversely impact detection rates, Dr. Lee and his colleagues didn’t know because they measured only the colonoscopic screening and surveillance activities. “The reported lack of an association with time of day would argue against this being a substantial factor in [this] study,” they wrote.

“The fact that increased adenoma detection was found only for screening colonoscopy examinations raises the question of whether endoscopists were systematically more vigilant during screening procedures, although the higher observed adenoma detection rates for surveillance examinations suggest otherwise,” the investigators wrote.

None of the investigators listed had any relevant disclosures.
 

[email protected]

On Twitter @whitneymcknight

Neither time of day, nor number of procedures performed by the clinician impacted adenoma detection rates in a large community-based setting, a study has shown.

Previously, mixed and scanty data on whether endoscopist fatigue correlates with colonoscopy quality in a community-based setting – where the majority of colonoscopies are performed – brought into question the link between a clinician’s detection rates and patient mortality rates due to interval cancers. Colorectal cancer is the second leading cause of cancer death in the U.S.

The most recent recommended adenoma detection rates – considered benchmarks of colonoscopic quality – are at or above 20% in men and at or above 30% in women, according to the American College of Gastroenterology.

A new study published online in Gastrointestinal Endoscopy, however, indicates that the endoscopists working in a large, integrated, community-based health care system exceeded those quality benchmarks.

Gastroenterologist Alexander T. Lee, MD, and his colleagues identified 126 gastroenterologists in the health system, Kaiser Permanente Northern California, who performed an average of six endoscopy procedures per day – 259,064 in all – between 2010 and 2013, including 76,445 screenings and surveillance colonoscopies. They found that per physician, adenoma detection rates for screening colonoscopy examinations averaged 28.9% and 45.4% for surveillance examinations. By patient gender, the average detection rates per screening were 34.8% for men and 24.0% for women; detection rates per surveillance, the rates were 51.1% for men and 37.8% for women.

After adjusting for confounders, the investigators analyzed each physician’s average adenoma detection rates in association with the time of day each GI procedure was performed, the number of GI procedures performed before each colonoscopy, and the level of complexity of any prior procedures performed at the time of the screening or surveillance colonoscopy. Dr. Lee and his coinvestigators also found that compared with morning examinations, afternoon colonoscopies were not associated with lower adenoma detection for screening examinations, surveillance examinations, or their combination (odds ratio for combination, 0.99; 95% confidence interval, 0.96-1.03). Additionally, neither the number of procedures performed before a given colonoscopy, nor a prior procedure’s complexity, was inversely associated with adenoma detection (OR for detection rates late in the day vs. first procedure of the day, 0.99; 95% CI, 0.94-1.04).

In systems where physicians have larger daily GI procedure loads, there could be an adverse impact on adenoma detection rates, wrote Dr. Lee and his coauthors, but they also noted that quality could similarly be diluted by a lower ratio of procedures to clinician, as well. Whether other demands on a physician’s time, such as other clinical procedures or office tasks, might adversely impact detection rates, Dr. Lee and his colleagues didn’t know because they measured only the colonoscopic screening and surveillance activities. “The reported lack of an association with time of day would argue against this being a substantial factor in [this] study,” they wrote.

“The fact that increased adenoma detection was found only for screening colonoscopy examinations raises the question of whether endoscopists were systematically more vigilant during screening procedures, although the higher observed adenoma detection rates for surveillance examinations suggest otherwise,” the investigators wrote.

None of the investigators listed had any relevant disclosures.
 

[email protected]

On Twitter @whitneymcknight

BOSTON – For rheumatologists, the primary selling points of biosimilar agents are their presumed efficacy and safety, and their promised cost savings, compared with the reference product, an original biologic agent.

But market forces, patient worries, and provider concerns threaten to file off at least some of biosimilars’ presumed competitive edge, says a rheumatologist involved in the development of biosimilars to treat rheumatic diseases.

“The availability of lower-priced biosimilars, if they’re truly lower priced, should decrease the cost of treating patients; if they’re not lower cost, then this advantage is not holding true,” said Jonathan Kay, MD, professor of medicine at UMass Memorial Medical Center in Worcester.

Misperceptions

A common concern among patients and uninformed providers is that biosimilars are the same as biomimics – cheap, usually foreign-made knockoffs of existing drugs that have not undergone regulatory scrutiny and may be neither effective nor safe.

“Biomimics scare patients and scare physicians,” he said, “and misunderstanding of the regulatory approval process, or lack of understanding of the regulatory review or approval process, also intimidates individuals about biosimilars.”

Acceptance of biosimilars is also hampered by a lack of long-term, real-world efficacy and safety data. This is due, in part, to the “inverted pyramid” nature of the biosimilar development and approval process, which starts with myriad analytical, chemical, and functional characterization studies; nonclinical studies; and pharmacokinetic and pharmacodynamic analyses, but only one or two clinical trials. In contrast, the development process for innovator biologics starts with molecular characterization, then moves through the traditional drug development stages of laboratory and preclinical studies, phase I and II trials, and finally phase III registration trials and post-marketing studies.

Because most of the drug development for biosimilars happens behind the scenes, patients and their physicians are often leery about the finished product, no matter how rigorously it was developed. Similarly, there is a paucity of data on long-term immunogenicity of biosimilars, Dr. Kay noted.

Extrapolating about extrapolation

The idea of extrapolation of indications for biosimilars is also an alien concept to many. Simply put, if a reference product is approved for rheumatoid arthritis and has additional indications for treatment of psoriatic arthritis, the approved biosimilar to the original can be extrapolated to be effective against the same indications, even if it has only been tested against one of the indications.

“We have a tremendous amount of clinical experience not only in randomized, controlled clinical trials but also years of marketing experience showing that the reference product is effective and safe for each of the indications for which it’s been approved, and knowing that the biosimilar is essentially like another [manufacturing] run of the reference product allows us to extrapolate indications. But until you become comfortable with accepting that concept, it is certainly a barrier to biosimilars,” he said.

Patients are also scared by the issue of interchangeability, which would allow pharmacists to substitute one product for another without approval of either the patient or the prescribing physician. However, there are currently no biosimilar agents approved as interchangeable by the Food and Drug Administration.

What cost savings?

In the United States, the price of marketed biosimilars has been only 15% lower than that of the reference product, Dr. Kay noted, and multiple discount programs and rebates offered by marketers of the reference product make it difficult to figure out the actual costs of the drugs to payers and whether biosimilars are actually any cheaper.

Additionally, clinicians may be reluctant to adopt biosimilars because of a Centers for Medicare & Medicaid Services billing quirk that currently offers only a single “J” code with a blended reimbursement for all biosimilar agents of a reference product, regardless of cost differences.

Nordic competition model

Dr. Kay pointed to the Norwegian Tender System as a model for using biosimilars to drive down drug costs.

The Norwegian Drug Procurement Cooperation (LIS) annually procures drugs for all publicly funded hospitals, which ensures that prices offered to hospitals for patent-protected medicines are lower than those offered for distribution to wholesalers or pharmacies. Under this system, cost is the driving factor, assuming that drugs in a similar class have similar efficacy and safety, he said.

In 2015, when Norway was purchasing infliximab, it chose Remsima, the biosimilar, over the reference product Remicade, resulting in a 69% cost saving.

The potential interchangeability of Remsima and Remicade in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and chronic plaque psoriasis is currently being explored in the NOR-SWITCH trial.

Dr. Kay disclosed receiving institutional grants from AbbVie, Genentech, Roche Laboratories, and UCB, and serving as a consultant for those companies.

BOSTON – For rheumatologists, the primary selling points of biosimilar agents are their presumed efficacy and safety, and their promised cost savings, compared with the reference product, an original biologic agent.

But market forces, patient worries, and provider concerns threaten to file off at least some of biosimilars’ presumed competitive edge, says a rheumatologist involved in the development of biosimilars to treat rheumatic diseases.

“The availability of lower-priced biosimilars, if they’re truly lower priced, should decrease the cost of treating patients; if they’re not lower cost, then this advantage is not holding true,” said Jonathan Kay, MD, professor of medicine at UMass Memorial Medical Center in Worcester.

Misperceptions

A common concern among patients and uninformed providers is that biosimilars are the same as biomimics – cheap, usually foreign-made knockoffs of existing drugs that have not undergone regulatory scrutiny and may be neither effective nor safe.

“Biomimics scare patients and scare physicians,” he said, “and misunderstanding of the regulatory approval process, or lack of understanding of the regulatory review or approval process, also intimidates individuals about biosimilars.”

Acceptance of biosimilars is also hampered by a lack of long-term, real-world efficacy and safety data. This is due, in part, to the “inverted pyramid” nature of the biosimilar development and approval process, which starts with myriad analytical, chemical, and functional characterization studies; nonclinical studies; and pharmacokinetic and pharmacodynamic analyses, but only one or two clinical trials. In contrast, the development process for innovator biologics starts with molecular characterization, then moves through the traditional drug development stages of laboratory and preclinical studies, phase I and II trials, and finally phase III registration trials and post-marketing studies.

Because most of the drug development for biosimilars happens behind the scenes, patients and their physicians are often leery about the finished product, no matter how rigorously it was developed. Similarly, there is a paucity of data on long-term immunogenicity of biosimilars, Dr. Kay noted.

Extrapolating about extrapolation

The idea of extrapolation of indications for biosimilars is also an alien concept to many. Simply put, if a reference product is approved for rheumatoid arthritis and has additional indications for treatment of psoriatic arthritis, the approved biosimilar to the original can be extrapolated to be effective against the same indications, even if it has only been tested against one of the indications.

“We have a tremendous amount of clinical experience not only in randomized, controlled clinical trials but also years of marketing experience showing that the reference product is effective and safe for each of the indications for which it’s been approved, and knowing that the biosimilar is essentially like another [manufacturing] run of the reference product allows us to extrapolate indications. But until you become comfortable with accepting that concept, it is certainly a barrier to biosimilars,” he said.

Patients are also scared by the issue of interchangeability, which would allow pharmacists to substitute one product for another without approval of either the patient or the prescribing physician. However, there are currently no biosimilar agents approved as interchangeable by the Food and Drug Administration.

What cost savings?

In the United States, the price of marketed biosimilars has been only 15% lower than that of the reference product, Dr. Kay noted, and multiple discount programs and rebates offered by marketers of the reference product make it difficult to figure out the actual costs of the drugs to payers and whether biosimilars are actually any cheaper.

Additionally, clinicians may be reluctant to adopt biosimilars because of a Centers for Medicare & Medicaid Services billing quirk that currently offers only a single “J” code with a blended reimbursement for all biosimilar agents of a reference product, regardless of cost differences.

Nordic competition model

Dr. Kay pointed to the Norwegian Tender System as a model for using biosimilars to drive down drug costs.

The Norwegian Drug Procurement Cooperation (LIS) annually procures drugs for all publicly funded hospitals, which ensures that prices offered to hospitals for patent-protected medicines are lower than those offered for distribution to wholesalers or pharmacies. Under this system, cost is the driving factor, assuming that drugs in a similar class have similar efficacy and safety, he said.

In 2015, when Norway was purchasing infliximab, it chose Remsima, the biosimilar, over the reference product Remicade, resulting in a 69% cost saving.

The potential interchangeability of Remsima and Remicade in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and chronic plaque psoriasis is currently being explored in the NOR-SWITCH trial.

Dr. Kay disclosed receiving institutional grants from AbbVie, Genentech, Roche Laboratories, and UCB, and serving as a consultant for those companies.

BOSTON – For rheumatologists, the primary selling points of biosimilar agents are their presumed efficacy and safety, and their promised cost savings, compared with the reference product, an original biologic agent.

But market forces, patient worries, and provider concerns threaten to file off at least some of biosimilars’ presumed competitive edge, says a rheumatologist involved in the development of biosimilars to treat rheumatic diseases.

“The availability of lower-priced biosimilars, if they’re truly lower priced, should decrease the cost of treating patients; if they’re not lower cost, then this advantage is not holding true,” said Jonathan Kay, MD, professor of medicine at UMass Memorial Medical Center in Worcester.

Misperceptions

A common concern among patients and uninformed providers is that biosimilars are the same as biomimics – cheap, usually foreign-made knockoffs of existing drugs that have not undergone regulatory scrutiny and may be neither effective nor safe.

“Biomimics scare patients and scare physicians,” he said, “and misunderstanding of the regulatory approval process, or lack of understanding of the regulatory review or approval process, also intimidates individuals about biosimilars.”

Acceptance of biosimilars is also hampered by a lack of long-term, real-world efficacy and safety data. This is due, in part, to the “inverted pyramid” nature of the biosimilar development and approval process, which starts with myriad analytical, chemical, and functional characterization studies; nonclinical studies; and pharmacokinetic and pharmacodynamic analyses, but only one or two clinical trials. In contrast, the development process for innovator biologics starts with molecular characterization, then moves through the traditional drug development stages of laboratory and preclinical studies, phase I and II trials, and finally phase III registration trials and post-marketing studies.

Because most of the drug development for biosimilars happens behind the scenes, patients and their physicians are often leery about the finished product, no matter how rigorously it was developed. Similarly, there is a paucity of data on long-term immunogenicity of biosimilars, Dr. Kay noted.

Extrapolating about extrapolation

The idea of extrapolation of indications for biosimilars is also an alien concept to many. Simply put, if a reference product is approved for rheumatoid arthritis and has additional indications for treatment of psoriatic arthritis, the approved biosimilar to the original can be extrapolated to be effective against the same indications, even if it has only been tested against one of the indications.

“We have a tremendous amount of clinical experience not only in randomized, controlled clinical trials but also years of marketing experience showing that the reference product is effective and safe for each of the indications for which it’s been approved, and knowing that the biosimilar is essentially like another [manufacturing] run of the reference product allows us to extrapolate indications. But until you become comfortable with accepting that concept, it is certainly a barrier to biosimilars,” he said.

Patients are also scared by the issue of interchangeability, which would allow pharmacists to substitute one product for another without approval of either the patient or the prescribing physician. However, there are currently no biosimilar agents approved as interchangeable by the Food and Drug Administration.

What cost savings?

In the United States, the price of marketed biosimilars has been only 15% lower than that of the reference product, Dr. Kay noted, and multiple discount programs and rebates offered by marketers of the reference product make it difficult to figure out the actual costs of the drugs to payers and whether biosimilars are actually any cheaper.

Additionally, clinicians may be reluctant to adopt biosimilars because of a Centers for Medicare & Medicaid Services billing quirk that currently offers only a single “J” code with a blended reimbursement for all biosimilar agents of a reference product, regardless of cost differences.

Nordic competition model

Dr. Kay pointed to the Norwegian Tender System as a model for using biosimilars to drive down drug costs.

The Norwegian Drug Procurement Cooperation (LIS) annually procures drugs for all publicly funded hospitals, which ensures that prices offered to hospitals for patent-protected medicines are lower than those offered for distribution to wholesalers or pharmacies. Under this system, cost is the driving factor, assuming that drugs in a similar class have similar efficacy and safety, he said.

In 2015, when Norway was purchasing infliximab, it chose Remsima, the biosimilar, over the reference product Remicade, resulting in a 69% cost saving.

The potential interchangeability of Remsima and Remicade in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and chronic plaque psoriasis is currently being explored in the NOR-SWITCH trial.

Dr. Kay disclosed receiving institutional grants from AbbVie, Genentech, Roche Laboratories, and UCB, and serving as a consultant for those companies.

LOS ANGELES – A newer blood test (GeneStrat from Biodesix) identified genetic mutations in lung tumors in about 24 hours, allowing for an early start of mutation-specific chemotherapy, in an investigation from Gundersen Health System in La Crosse, Wis.

Interventional pulmonologists drew blood samples when they performed biopsies on 84 patients with highly suspicious lung nodules and submitted both blood and tissue for mutation analysis. The blood was analyzed by Biodesix, the maker of GeneStrat, a commercially available digital droplet polymerase change reaction assay launched in 2015. The company sent the results back in an average of 24.1 hours, and all within 72 hours. The mutation results from tissue analysis took 2-3 weeks.

Fifteen patients (18%) had actionable epidermal growth factor receptor, anaplastic lymphoma kinase, or K-Ras protein gene mutations, and were candidates for targeted therapy. Compared with tissue testing, the blood assay had a sensitivity of 88% and a specificity of 99%. The tissue testing picked up two mutations missed by blood testing. One of the two mutations is rare and was not included in the blood assay. Meanwhile, the assay caught a mutation missed on tissue analysis.

M. Alexander Otto/Frontline Medical News

[email protected]

LOS ANGELES – A newer blood test (GeneStrat from Biodesix) identified genetic mutations in lung tumors in about 24 hours, allowing for an early start of mutation-specific chemotherapy, in an investigation from Gundersen Health System in La Crosse, Wis.

Interventional pulmonologists drew blood samples when they performed biopsies on 84 patients with highly suspicious lung nodules and submitted both blood and tissue for mutation analysis. The blood was analyzed by Biodesix, the maker of GeneStrat, a commercially available digital droplet polymerase change reaction assay launched in 2015. The company sent the results back in an average of 24.1 hours, and all within 72 hours. The mutation results from tissue analysis took 2-3 weeks.

Fifteen patients (18%) had actionable epidermal growth factor receptor, anaplastic lymphoma kinase, or K-Ras protein gene mutations, and were candidates for targeted therapy. Compared with tissue testing, the blood assay had a sensitivity of 88% and a specificity of 99%. The tissue testing picked up two mutations missed by blood testing. One of the two mutations is rare and was not included in the blood assay. Meanwhile, the assay caught a mutation missed on tissue analysis.

M. Alexander Otto/Frontline Medical News

[email protected]

LOS ANGELES – A newer blood test (GeneStrat from Biodesix) identified genetic mutations in lung tumors in about 24 hours, allowing for an early start of mutation-specific chemotherapy, in an investigation from Gundersen Health System in La Crosse, Wis.

Interventional pulmonologists drew blood samples when they performed biopsies on 84 patients with highly suspicious lung nodules and submitted both blood and tissue for mutation analysis. The blood was analyzed by Biodesix, the maker of GeneStrat, a commercially available digital droplet polymerase change reaction assay launched in 2015. The company sent the results back in an average of 24.1 hours, and all within 72 hours. The mutation results from tissue analysis took 2-3 weeks.

Fifteen patients (18%) had actionable epidermal growth factor receptor, anaplastic lymphoma kinase, or K-Ras protein gene mutations, and were candidates for targeted therapy. Compared with tissue testing, the blood assay had a sensitivity of 88% and a specificity of 99%. The tissue testing picked up two mutations missed by blood testing. One of the two mutations is rare and was not included in the blood assay. Meanwhile, the assay caught a mutation missed on tissue analysis.

M. Alexander Otto/Frontline Medical News

[email protected]

Clinical Question: Is there a mortality difference in nondiabetic patients with multivessel coronary artery disease (CAD) treated with coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI)?

Background: Randomized clinical trials have shown a mortality benefit of CABG over PCI with drug-eluting stents (DES) for diabetic patients. The best strategy for nondiabetics, however, has not been well established.

Study Design: Pooled individual patient data from two large randomized clinical trials.

Setting: Multicenter, multinational (Europe, United States, Asia).

Synopsis: Excluding patients with left main disease, a total of 1,275 nondiabetic patients with two- or three-vessel CAD were analyzed. After median follow-up of 61 months, the CABG group had significantly fewer deaths from any cause (hazard ratio [HR], 0.65; 95% CI, 0.43–0.98; P=0.039) as well as fewer deaths from cardiac causes (HR, 0.41; 95% CI, 0.25–0.78; P=0.005) when compared to PCI with DES. The benefit was primarily seen at five-year follow-up in patients with intermediate to severe disease, with a nonsignificant difference detected in patients with less severe disease.

Despite the increasing popularity of DES, this study suggests that for nondiabetic patients with CAD, there is a mortality benefit at five years favoring CABG over PCI with DES. However, in this study stents used for PCI included both older and newer generation DES; a study using only newer DES may reduce the differences in outcomes between the groups.

Bottom Line: Five-year mortality is lower in nondiabetic patients with multivessel CAD treated with CABG compared with PCI with DES.

Citation: Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol. 2016;68(1):29-36.

Clinical Question: Is there a mortality difference in nondiabetic patients with multivessel coronary artery disease (CAD) treated with coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI)?

Background: Randomized clinical trials have shown a mortality benefit of CABG over PCI with drug-eluting stents (DES) for diabetic patients. The best strategy for nondiabetics, however, has not been well established.

Study Design: Pooled individual patient data from two large randomized clinical trials.

Setting: Multicenter, multinational (Europe, United States, Asia).

Synopsis: Excluding patients with left main disease, a total of 1,275 nondiabetic patients with two- or three-vessel CAD were analyzed. After median follow-up of 61 months, the CABG group had significantly fewer deaths from any cause (hazard ratio [HR], 0.65; 95% CI, 0.43–0.98; P=0.039) as well as fewer deaths from cardiac causes (HR, 0.41; 95% CI, 0.25–0.78; P=0.005) when compared to PCI with DES. The benefit was primarily seen at five-year follow-up in patients with intermediate to severe disease, with a nonsignificant difference detected in patients with less severe disease.

Despite the increasing popularity of DES, this study suggests that for nondiabetic patients with CAD, there is a mortality benefit at five years favoring CABG over PCI with DES. However, in this study stents used for PCI included both older and newer generation DES; a study using only newer DES may reduce the differences in outcomes between the groups.

Bottom Line: Five-year mortality is lower in nondiabetic patients with multivessel CAD treated with CABG compared with PCI with DES.

Citation: Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol. 2016;68(1):29-36.

Clinical Question: Is there a mortality difference in nondiabetic patients with multivessel coronary artery disease (CAD) treated with coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI)?

Background: Randomized clinical trials have shown a mortality benefit of CABG over PCI with drug-eluting stents (DES) for diabetic patients. The best strategy for nondiabetics, however, has not been well established.

Study Design: Pooled individual patient data from two large randomized clinical trials.

Setting: Multicenter, multinational (Europe, United States, Asia).

Synopsis: Excluding patients with left main disease, a total of 1,275 nondiabetic patients with two- or three-vessel CAD were analyzed. After median follow-up of 61 months, the CABG group had significantly fewer deaths from any cause (hazard ratio [HR], 0.65; 95% CI, 0.43–0.98; P=0.039) as well as fewer deaths from cardiac causes (HR, 0.41; 95% CI, 0.25–0.78; P=0.005) when compared to PCI with DES. The benefit was primarily seen at five-year follow-up in patients with intermediate to severe disease, with a nonsignificant difference detected in patients with less severe disease.

Despite the increasing popularity of DES, this study suggests that for nondiabetic patients with CAD, there is a mortality benefit at five years favoring CABG over PCI with DES. However, in this study stents used for PCI included both older and newer generation DES; a study using only newer DES may reduce the differences in outcomes between the groups.

Bottom Line: Five-year mortality is lower in nondiabetic patients with multivessel CAD treated with CABG compared with PCI with DES.

Citation: Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol. 2016;68(1):29-36.

Clinical Question: What is the incidence of neutropenia in patients treated with prolonged courses of ceftaroline?

Background: Ceftaroline, a new broad-spectrum cephalosporin antibiotic, is FDA approved for the treatment of skin and soft-tissue infections and community-acquired pneumonia (CAP). Other than a few case reports, previous studies have not assessed the incidence of neutropenia in patients receiving ceftaroline for off-label indications or for prolonged courses.

Study Design: Retrospective chart review.

Setting: Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

Synopsis: The authors identified 67 patients who received ceftaroline for seven or more consecutive days. Overall, ceftaroline exposure for two or more weeks was associated with a 10%–14% incidence of neutropenia (absolute neutrophil count less than 1,800 cells/mm3), and ceftaroline exposure for three or more weeks was associated with a 21% incidence of neutropenia. Both the mean duration of ceftaroline exposure and the total number of ceftaroline doses were associated with incident neutropenia.

This is the first study to systematically assess the incidence of ceftaroline-associated neutropenia. The data support a correlation between cumulative ceftaroline exposure and neutropenia. Hospitalists managing patients with prolonged courses of ceftaroline should carefully monitor hematologic studies during treatment.

Bottom Line: The overall rate of neutropenia in patients receiving prolonged courses of ceftaroline is significant, and it is associated with duration of ceftaroline exposure and total number of doses received.

Citation: Furtek KJ, Kubiak DW, Barra M, Varughese C, Ashbaugh CD, Koo S. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71(7):2010-2013.

Short Take

New Guidelines from IDSA/ATS for Patients with Community-Acquired Pneumonia Can Safely Be Implemented for Hospitalized Patients

A multicenter, non-inferiority randomized clinical trial of 312 patients with community-acquired pneumonia (CAP) found that stopping antibiotics after five days was not associated with worse outcomes and may reduce readmissions.

Citation: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

Clinical Question: What is the incidence of neutropenia in patients treated with prolonged courses of ceftaroline?

Background: Ceftaroline, a new broad-spectrum cephalosporin antibiotic, is FDA approved for the treatment of skin and soft-tissue infections and community-acquired pneumonia (CAP). Other than a few case reports, previous studies have not assessed the incidence of neutropenia in patients receiving ceftaroline for off-label indications or for prolonged courses.

Study Design: Retrospective chart review.

Setting: Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

Synopsis: The authors identified 67 patients who received ceftaroline for seven or more consecutive days. Overall, ceftaroline exposure for two or more weeks was associated with a 10%–14% incidence of neutropenia (absolute neutrophil count less than 1,800 cells/mm3), and ceftaroline exposure for three or more weeks was associated with a 21% incidence of neutropenia. Both the mean duration of ceftaroline exposure and the total number of ceftaroline doses were associated with incident neutropenia.

This is the first study to systematically assess the incidence of ceftaroline-associated neutropenia. The data support a correlation between cumulative ceftaroline exposure and neutropenia. Hospitalists managing patients with prolonged courses of ceftaroline should carefully monitor hematologic studies during treatment.

Bottom Line: The overall rate of neutropenia in patients receiving prolonged courses of ceftaroline is significant, and it is associated with duration of ceftaroline exposure and total number of doses received.

Citation: Furtek KJ, Kubiak DW, Barra M, Varughese C, Ashbaugh CD, Koo S. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71(7):2010-2013.

Short Take

New Guidelines from IDSA/ATS for Patients with Community-Acquired Pneumonia Can Safely Be Implemented for Hospitalized Patients

A multicenter, non-inferiority randomized clinical trial of 312 patients with community-acquired pneumonia (CAP) found that stopping antibiotics after five days was not associated with worse outcomes and may reduce readmissions.

Citation: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

Clinical Question: What is the incidence of neutropenia in patients treated with prolonged courses of ceftaroline?

Background: Ceftaroline, a new broad-spectrum cephalosporin antibiotic, is FDA approved for the treatment of skin and soft-tissue infections and community-acquired pneumonia (CAP). Other than a few case reports, previous studies have not assessed the incidence of neutropenia in patients receiving ceftaroline for off-label indications or for prolonged courses.

Study Design: Retrospective chart review.

Setting: Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

Synopsis: The authors identified 67 patients who received ceftaroline for seven or more consecutive days. Overall, ceftaroline exposure for two or more weeks was associated with a 10%–14% incidence of neutropenia (absolute neutrophil count less than 1,800 cells/mm3), and ceftaroline exposure for three or more weeks was associated with a 21% incidence of neutropenia. Both the mean duration of ceftaroline exposure and the total number of ceftaroline doses were associated with incident neutropenia.

This is the first study to systematically assess the incidence of ceftaroline-associated neutropenia. The data support a correlation between cumulative ceftaroline exposure and neutropenia. Hospitalists managing patients with prolonged courses of ceftaroline should carefully monitor hematologic studies during treatment.

Bottom Line: The overall rate of neutropenia in patients receiving prolonged courses of ceftaroline is significant, and it is associated with duration of ceftaroline exposure and total number of doses received.

Citation: Furtek KJ, Kubiak DW, Barra M, Varughese C, Ashbaugh CD, Koo S. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71(7):2010-2013.

Short Take

New Guidelines from IDSA/ATS for Patients with Community-Acquired Pneumonia Can Safely Be Implemented for Hospitalized Patients

A multicenter, non-inferiority randomized clinical trial of 312 patients with community-acquired pneumonia (CAP) found that stopping antibiotics after five days was not associated with worse outcomes and may reduce readmissions.

Citation: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

Flow cytometry using
laser beam
Photo courtesy of NIH

NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.

The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.

“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”

Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.

In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.

History of MRD analysis

The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10^-4) leukocytes, regardless of the tissue used.

Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.

Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.

“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.

Technologies

Several technologies can be used to assess MRD.

Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.

Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.

“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.

HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.

Flow cytometry and HTS

A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.

According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10^-4).

Assays had to be independent and compatible with older, established therapies as well as newer treatments.

For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).

Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.

And while PCR is more sensitive than flow cytometry (sensitive to 10^-5 to 10^-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.

The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials. 

They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
 
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.

The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10^-4) level.

Peripheral blood or bone marrow?

“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”

Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.

Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the  bone marrow (PB-/BM-) (Rawstron abstract S794).

But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.

And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.

“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.

Prognostic value of MRD assessment

Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.

And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.

Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.

In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).

“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.

Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.

And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.

In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.

For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.

“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”

Flow cytometry using
laser beam
Photo courtesy of NIH

NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.

The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.

“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”

Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.

In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.

History of MRD analysis

The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10^-4) leukocytes, regardless of the tissue used.

Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.

Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.

“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.

Technologies

Several technologies can be used to assess MRD.

Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.

Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.

“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.

HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.

Flow cytometry and HTS

A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.

According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10^-4).

Assays had to be independent and compatible with older, established therapies as well as newer treatments.

For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).

Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.

And while PCR is more sensitive than flow cytometry (sensitive to 10^-5 to 10^-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.

The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials. 

They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
 
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.

The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10^-4) level.

Peripheral blood or bone marrow?

“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”

Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.

Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the  bone marrow (PB-/BM-) (Rawstron abstract S794).

But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.

And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.

“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.

Prognostic value of MRD assessment

Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.

And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.

Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.

In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).

“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.

Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.

And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.

In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.

For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.

“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”

Flow cytometry using
laser beam
Photo courtesy of NIH

NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.

The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.

“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”

Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.

In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.

History of MRD analysis

The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10^-4) leukocytes, regardless of the tissue used.

Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.

Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.

“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.

Technologies

Several technologies can be used to assess MRD.

Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.

Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.

“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.

HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.

Flow cytometry and HTS

A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.

According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10^-4).

Assays had to be independent and compatible with older, established therapies as well as newer treatments.

For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).

Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.

And while PCR is more sensitive than flow cytometry (sensitive to 10^-5 to 10^-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.

The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials. 

They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
 
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.

The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10^-4) level.

Peripheral blood or bone marrow?

“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”

Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.

Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the  bone marrow (PB-/BM-) (Rawstron abstract S794).

But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.

And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.

“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.

Prognostic value of MRD assessment

Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.

And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.

Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.

In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).

“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.

Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.

And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.

In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.

For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.

“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”

Micrograph showing

Plasmodium falciparum

Image from CDC/Mae Melvin

Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.

Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.

Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.

However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.

The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.

About resistance

The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.

However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.

Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.

Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.

Plasmepsin genes

In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.

The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.

The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.

The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.

Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.

Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.

“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”

“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”

Exo-E415G variant

The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.

The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).

The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.

Parasites were more likely to survive exposure to piperaquine if they had 2 or more copies of the plasmepsin 2 and plasmepsin 3 genes, as well as the exo-E415G variant on chromosome 13.

Similarly, in a further analysis of 133 patient samples, the investigators found that individuals infected with parasites carrying multiple copies of the plasmepsin genes were much more likely to fail treatment with dihydroartemisinin-piperaquine, as were individuals who had parasites with the exo-E415G variant.

The team also noted that the prevalence of exo-E415G and plasmepsin 2-3 markers has risen substantially in recent years in Pursat and Preah Vihear, where artemisinin resistance is common and dihydroartemisinin-piperaquine has been the frontline treatment for at least 6 years.

“By surveying the piperaquine resistance marker across Southeast Asia in real-time, we can identify those areas where dihydroartemisinin-piperaquine will not be effective, and this could enable national malaria control programs to immediately recommend alternative therapies, such as artesunate-mefloquine,” Dr Fairhurst said.

“This approach will be crucial to eliminating multidrug-resistant parasites in Southeast Asia before they spread to sub-Saharan Africa, where most of the world’s malaria transmission, illness, and death occur.”

Micrograph showing

Plasmodium falciparum

Image from CDC/Mae Melvin

Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.

Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.

Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.

However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.

The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.

About resistance

The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.

However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.

Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.

Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.

Plasmepsin genes

In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.

The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.

The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.

The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.

Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.

Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.

“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”

“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”

Exo-E415G variant

The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.

The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).

The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.

Parasites were more likely to survive exposure to piperaquine if they had 2 or more copies of the plasmepsin 2 and plasmepsin 3 genes, as well as the exo-E415G variant on chromosome 13.

Similarly, in a further analysis of 133 patient samples, the investigators found that individuals infected with parasites carrying multiple copies of the plasmepsin genes were much more likely to fail treatment with dihydroartemisinin-piperaquine, as were individuals who had parasites with the exo-E415G variant.

The team also noted that the prevalence of exo-E415G and plasmepsin 2-3 markers has risen substantially in recent years in Pursat and Preah Vihear, where artemisinin resistance is common and dihydroartemisinin-piperaquine has been the frontline treatment for at least 6 years.

“By surveying the piperaquine resistance marker across Southeast Asia in real-time, we can identify those areas where dihydroartemisinin-piperaquine will not be effective, and this could enable national malaria control programs to immediately recommend alternative therapies, such as artesunate-mefloquine,” Dr Fairhurst said.

“This approach will be crucial to eliminating multidrug-resistant parasites in Southeast Asia before they spread to sub-Saharan Africa, where most of the world’s malaria transmission, illness, and death occur.”

Micrograph showing

Plasmodium falciparum

Image from CDC/Mae Melvin

Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.

Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.

Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.

However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.

The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.

About resistance

The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.

However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.

Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.

Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.

Plasmepsin genes

In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.

The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.

The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.

The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.

Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.

Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.

“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”

“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”

Exo-E415G variant

The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.

The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).

The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.

Parasites were more likely to survive exposure to piperaquine if they had 2 or more copies of the plasmepsin 2 and plasmepsin 3 genes, as well as the exo-E415G variant on chromosome 13.

Similarly, in a further analysis of 133 patient samples, the investigators found that individuals infected with parasites carrying multiple copies of the plasmepsin genes were much more likely to fail treatment with dihydroartemisinin-piperaquine, as were individuals who had parasites with the exo-E415G variant.

The team also noted that the prevalence of exo-E415G and plasmepsin 2-3 markers has risen substantially in recent years in Pursat and Preah Vihear, where artemisinin resistance is common and dihydroartemisinin-piperaquine has been the frontline treatment for at least 6 years.

“By surveying the piperaquine resistance marker across Southeast Asia in real-time, we can identify those areas where dihydroartemisinin-piperaquine will not be effective, and this could enable national malaria control programs to immediately recommend alternative therapies, such as artesunate-mefloquine,” Dr Fairhurst said.

“This approach will be crucial to eliminating multidrug-resistant parasites in Southeast Asia before they spread to sub-Saharan Africa, where most of the world’s malaria transmission, illness, and death occur.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention, as it is popu­larly thought to be.¹

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Mindset. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they ar­ticulate and explain the meaning of the fortune?

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention, as it is popu­larly thought to be.¹

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Mindset. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they ar­ticulate and explain the meaning of the fortune?

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention, as it is popu­larly thought to be.¹

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Mindset. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they ar­ticulate and explain the meaning of the fortune?