Will Pass

Individuals who are younger when diagnosed with type 2 diabetes are at greater risk of cardiovascular disease and death, compared with those diagnosed at an older age, according to a retrospective study involving almost 2 million people.

People diagnosed with type 2 diabetes at age 40 or younger were at greatest risk of most outcomes, reported lead author Naveed Sattar, MD, PhD, professor of metabolic medicine, University of Glasgow, Scotland, and his colleagues. “Treatment target recommendations in regards to the risk factor control may need to be more aggressive in people developing diabetes at younger ages,” they wrote in Circulation. 

In contrast, developing type 2 diabetes over the age of 80 years had little impact on risks.

“[R]eassessment of treatment goals in elderly might be useful,” the investigators wrote. “Diabetes screening needs for the elderly (above 80) should also be reevaluated.”

The study involved 318,083 patients with type 2 diabetes registered  in the Swedish National Diabetes Registry between 1998 and 2012. Each patient was matched with 5 individuals from the general population based on sex, age, and country of residence, providing a control population of 1,575,108. Outcomes assessed included non-cardiovascular mortality, cardiovascular mortality, all causemortality, hospitalization for heart failure, coronary heart disease, stroke, atrial fibrillation, and acute myocardial infarction. Patients were followed for cardiovascular outcomes from 1998 to December 2013, while mortality surveillance continued through 2014.

In comparison with controls, patients 40 years or less had the highest excess risk of the most outcomes. *Excess risk of heart failure was elevated almost 5-fold (hazard ratio (HR), R 4.77), and risk of coronary heart disease wasn’t far behind (HR, 4.33). Risks of acute MI (HR, 3.41), stroke (HR, 3.58), and atrial fibrillation (HR, 1.95) were also elevated. Cardiovascular-related mortality was increased almost 3-fold (HR, 2.72), while total mortality (HR, 2.05) and non-cardiovascular mortality (HR, 1.95) were raised to a lesser degree.

“Thereafter, incremental risks generally declined with each higher decade age at diagnosis” of type 2 diabetes,” the investigators wrote.

After 80 years of age, all relative mortality risk factors dropped to less than 1, indicating lower risk than controls. Although non-fatal outcomes were still greater than 1 in this age group, these risks were “substantially attenuated compared with relative incremental risks in those diagnosed with T2DM at younger ages,” the investigators wrote.

The study was funded by the Swedish Association of Local Authorities Regions, the Swedish Heart and Lung Foundation, and the Swedish Research Council.

The investigators disclosed financial relationships with Amgen, AstraZeneca, Eli Lilly, and other pharmaceutical companies.

SOURCE: Sattar et al. Circulation. 2019 Apr 8. doi:10.1161/CIRCULATIONAHA.118.037885.

Individuals who are younger when diagnosed with type 2 diabetes are at greater risk of cardiovascular disease and death, compared with those diagnosed at an older age, according to a retrospective study involving almost 2 million people.

People diagnosed with type 2 diabetes at age 40 or younger were at greatest risk of most outcomes, reported lead author Naveed Sattar, MD, PhD, professor of metabolic medicine, University of Glasgow, Scotland, and his colleagues. “Treatment target recommendations in regards to the risk factor control may need to be more aggressive in people developing diabetes at younger ages,” they wrote in Circulation. 

In contrast, developing type 2 diabetes over the age of 80 years had little impact on risks.

“[R]eassessment of treatment goals in elderly might be useful,” the investigators wrote. “Diabetes screening needs for the elderly (above 80) should also be reevaluated.”

The study involved 318,083 patients with type 2 diabetes registered  in the Swedish National Diabetes Registry between 1998 and 2012. Each patient was matched with 5 individuals from the general population based on sex, age, and country of residence, providing a control population of 1,575,108. Outcomes assessed included non-cardiovascular mortality, cardiovascular mortality, all causemortality, hospitalization for heart failure, coronary heart disease, stroke, atrial fibrillation, and acute myocardial infarction. Patients were followed for cardiovascular outcomes from 1998 to December 2013, while mortality surveillance continued through 2014.

In comparison with controls, patients 40 years or less had the highest excess risk of the most outcomes. *Excess risk of heart failure was elevated almost 5-fold (hazard ratio (HR), R 4.77), and risk of coronary heart disease wasn’t far behind (HR, 4.33). Risks of acute MI (HR, 3.41), stroke (HR, 3.58), and atrial fibrillation (HR, 1.95) were also elevated. Cardiovascular-related mortality was increased almost 3-fold (HR, 2.72), while total mortality (HR, 2.05) and non-cardiovascular mortality (HR, 1.95) were raised to a lesser degree.

“Thereafter, incremental risks generally declined with each higher decade age at diagnosis” of type 2 diabetes,” the investigators wrote.

After 80 years of age, all relative mortality risk factors dropped to less than 1, indicating lower risk than controls. Although non-fatal outcomes were still greater than 1 in this age group, these risks were “substantially attenuated compared with relative incremental risks in those diagnosed with T2DM at younger ages,” the investigators wrote.

The study was funded by the Swedish Association of Local Authorities Regions, the Swedish Heart and Lung Foundation, and the Swedish Research Council.

The investigators disclosed financial relationships with Amgen, AstraZeneca, Eli Lilly, and other pharmaceutical companies.

SOURCE: Sattar et al. Circulation. 2019 Apr 8. doi:10.1161/CIRCULATIONAHA.118.037885.

Individuals who are younger when diagnosed with type 2 diabetes are at greater risk of cardiovascular disease and death, compared with those diagnosed at an older age, according to a retrospective study involving almost 2 million people.

People diagnosed with type 2 diabetes at age 40 or younger were at greatest risk of most outcomes, reported lead author Naveed Sattar, MD, PhD, professor of metabolic medicine, University of Glasgow, Scotland, and his colleagues. “Treatment target recommendations in regards to the risk factor control may need to be more aggressive in people developing diabetes at younger ages,” they wrote in Circulation. 

In contrast, developing type 2 diabetes over the age of 80 years had little impact on risks.

“[R]eassessment of treatment goals in elderly might be useful,” the investigators wrote. “Diabetes screening needs for the elderly (above 80) should also be reevaluated.”

The study involved 318,083 patients with type 2 diabetes registered  in the Swedish National Diabetes Registry between 1998 and 2012. Each patient was matched with 5 individuals from the general population based on sex, age, and country of residence, providing a control population of 1,575,108. Outcomes assessed included non-cardiovascular mortality, cardiovascular mortality, all causemortality, hospitalization for heart failure, coronary heart disease, stroke, atrial fibrillation, and acute myocardial infarction. Patients were followed for cardiovascular outcomes from 1998 to December 2013, while mortality surveillance continued through 2014.

In comparison with controls, patients 40 years or less had the highest excess risk of the most outcomes. *Excess risk of heart failure was elevated almost 5-fold (hazard ratio (HR), R 4.77), and risk of coronary heart disease wasn’t far behind (HR, 4.33). Risks of acute MI (HR, 3.41), stroke (HR, 3.58), and atrial fibrillation (HR, 1.95) were also elevated. Cardiovascular-related mortality was increased almost 3-fold (HR, 2.72), while total mortality (HR, 2.05) and non-cardiovascular mortality (HR, 1.95) were raised to a lesser degree.

“Thereafter, incremental risks generally declined with each higher decade age at diagnosis” of type 2 diabetes,” the investigators wrote.

After 80 years of age, all relative mortality risk factors dropped to less than 1, indicating lower risk than controls. Although non-fatal outcomes were still greater than 1 in this age group, these risks were “substantially attenuated compared with relative incremental risks in those diagnosed with T2DM at younger ages,” the investigators wrote.

The study was funded by the Swedish Association of Local Authorities Regions, the Swedish Heart and Lung Foundation, and the Swedish Research Council.

The investigators disclosed financial relationships with Amgen, AstraZeneca, Eli Lilly, and other pharmaceutical companies.

SOURCE: Sattar et al. Circulation. 2019 Apr 8. doi:10.1161/CIRCULATIONAHA.118.037885.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Targeting circulating parasitic histones may hold promise for patients with cerebral malaria (CM), according to investigators.

A retrospective study, involving over 300 individuals, compared parasitic histone concentrations among patients with various forms of malaria and non-malarial illnesses, in addition to healthy controls, finding that elevated histone levels were associated with malarial disease severity and death, reported Simon Abrams, PhD, of the University of Liverpool, UK, a coauthor of the study. He noted that this research could guide the development of treatment strategies for hundreds of thousands of patients each year, particularly children.

“Cerebral malaria is the most severe form of Plasmodium falciparum infection, and despite effective anti-malarial therapy, between 10% and 20% of children that develop cerebral malaria die,” Dr. Abrams said during his presentation at the annual meeting of the British Society for Haematology. “This accounts for a huge amount of deaths per annum. Around 400,000 malarial deaths are in children in subSaharan Africa, and death typically occurs within 24 hours of hospital admission.”

In CM, the blood-brain barrier deteriorates, leading to brain swelling, hemorrhaging, clot formation, and in many cases, death, Dr. Abrams said. CM patients with the worst outcomes typically have retinal abnormalities on fundic exam, granting the disease subtype “retinopathy-positive.”

Aided by colleagues in Malawi, the investigators gathered over 300 patient samples for analysis. They found that patients with retinopathy-positive CM had higher mean extracellular histone levels than retinopathy-negative CM patients and healthy controls (22.6 mcg/ml, 6.31 mcg/ml, and 0.33 mcg/ml, respectively). In addition, retinopathy-positive CM patients who died had significantly higher levels of circulating histones, compared with similar patients who survived (35.7 mcg/ml vs. 21.6 mcg/ml).

These findings translated to predictive capability, as the investigators showed that patients with CM who had elevated histones when admitted to the hospital were at a higher risk of death than those with normal histone levels (P = .04). Unlike patients with CM, patients with uncomplicated malaria had relatively low histone levels (0.57 mcg/ml), as did patients with mild non-malarial febrile illness (1.73 mcg/ml) and non-malarial coma (1.73 mcg/ml).

During his presentation, Dr. Abrams elaborated on the origins of these histones and how they contribute to poor outcomes in patients.

“Histones are small positively charged proteins that bind to negatively charged DNA,” Dr. Abrams said. “Typically, they are found within the cell nucleus, where they are involved in the packaging of DNA. However, during cell death and cell damage, histones are released from the nucleus, extracellularly, and we find that they are very much elevated in critically ill patients that have undergone huge amounts of cell death and damage.”

Once in circulation, histones can make a bad situation even worse.

“Work by ourselves and others around the globe have found that when circulating histones are elevated in these critically ill patients, they’re extremely toxic,” Dr. Abrams said. “Histones can induce endothelial damage and vascular permeability.” In addition, he pointed out that histones are pro-inflammatory and pro-coagulant. “If you bring all of these phenomena together,” he pointed out, “histones induce organ injury and mortality in critically ill patients.”

“The current hypothesis is that if you’re treating patients with these antimalarials, and it’s killing off the parasite, it may cause the histones to be released, which is actually worse for certain patients,” Dr. Abrams explained.

Based on this hypothesis, the investigators developed an anti-histone therapy.

“We’ve got a small peptide that we use to bind to the histones that reduces their toxicity,” Dr. Abrams said. “If we coincubate the serum of [CM] patients with our anti-histone reagent and then put this onto a monolayer of endothelial cells, we see that this toxicity is inhibited. Therefore, this is suggestive that a major toxic factor within these patients are the extracellular histones.”

Providing additional support for the role of histones in cerebral toxicity, postmortem brain tissue from patients with CM showed localization of histones to the endothelium, which has been tied with increased permeability of vascular tissue. In addition, “we are seeing co-localization between the histones and the sequestration of the malarial parasite itself,” Dr. Abrams said. 

Concluding his presentation, he looked to the future.

“It’s difficult to get an animal model for malaria,” but he and his associates are currently working with other investigators to develop one. Once developed, the investigators plan on testing concurrent administration of anti-malarial therapy with antihistone therapy.

“What we’re hoping is that sometime in the future, maybe we’d be able to target circulating histones in this patient cohort to improve the survival of these patients,” Dr. Abrams said.

The investigators declared no conflicts of interest.

SOURCE: Moxon et al. BSH 2019. Abstract OR-034.

GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.

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Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.

This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.

Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.

Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.

All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m² or 500 mg) on day 1, bendamustine 70 mg/m² on days 1 and 2, and cytarabine 500 mg/m² on days 1 through 3, given in a 28-day cycle.

Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.

Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.

Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.

For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).

The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.

The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.

Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”

During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.

“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”

The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.

In an interview, Dr. Rule added perspective to these findings.

“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”

However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.

Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.

He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”

With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.

The investigators reported having no conflicts of interest.
 

GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.

Will Pass/MDedge News

Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.

This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.

Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.

Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.

All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m² or 500 mg) on day 1, bendamustine 70 mg/m² on days 1 and 2, and cytarabine 500 mg/m² on days 1 through 3, given in a 28-day cycle.

Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.

Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.

Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.

For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).

The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.

The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.

Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”

During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.

“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”

The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.

In an interview, Dr. Rule added perspective to these findings.

“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”

However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.

Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.

He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”

With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.

The investigators reported having no conflicts of interest.
 

GLASGOW – Patients with relapsed or refractory mantle cell lymphoma (MCL) who experience disease progression on a Bruton’s tyrosine kinase inhibitor (BTKi) may respond best to a combination of rituximab, bendamustine, and cytarabine (R-BAC), based on early results from an ongoing retrospective study.

Will Pass/MDedge News

Findings from the study, which were presented at the annual meeting of the British Society for Haematology, showed that R-BAC after BTKi failure had an overall response rate (ORR) of 90.5%.

This is a “remarkable response rate” according to the investigators, who cited previously reported response rates for other treatments ranging from 29% to 53%.

Treatment of relapsed/refractory MCL patients in the post-BTKi setting is an area of unmet clinical need, said senior author Simon Rule, MD, of the University of Plymouth, England. He noted that there is currently no consensus regarding best treatment strategy for this patient population.

Dr. Rule said that he and his colleagues have collected data on 30 patients so far, of which 22 were included in this early data release.

All patients received R-BAC between 2016 and 2018 at treatment centers in Italy and the United Kingdom. Treatment consisted of rituximab (375 mg/m² or 500 mg) on day 1, bendamustine 70 mg/m² on days 1 and 2, and cytarabine 500 mg/m² on days 1 through 3, given in a 28-day cycle.

Patients received R-BAC immediately after BTKi failure. Data were drawn from hospital records.

Analysis showed that the median patient age was 65 years, with a range from 43 to 79 years. Most patients were men (81.8%), 55.0% were high risk based on the Mantle Cell Lymphoma International Prognostic Index, and 22.7% had blastoid morphology.

Patients had a median of two prior systemic therapies, with a range from one to six lines. First-line therapies included rituximab in combination with HDAC (high-dose cytarabine containing regimen), CHOP, CVP, or ibrutinib. Nine patients (42.9%) had allogeneic stem cell transplantation (ASCT) after induction treatment.

For BTKi therapy, most patients received ibrutinib (n = 18), while the remainder received acalabrutinib, tirabrutinib or M7583. Most patients discontinued BTKi therapy because of disease progression (90.9%); two patients stopped because of a lack of response (9.1%).

The median number of R-BAC cycles received was four. Two patients started with attenuated doses and seven patients reduced doses after the first cycle. More than 70% of patients completed R-BAC treatment.

The estimated median progression-free survival was 7.3 months and estimated median overall survival was 11.2 months.

Although the investigators reported a complete response rate of 57.1%, they noted that this figure “may be exaggerated” because of a lack of bone marrow biopsy; however, they suggested that the overall response rate (90.5%) “should be accurate.”

During the course of treatment, 31.8% of patients required inpatient admission, 22.7% developed neutropenic fever, and 77.8% required transfusion support. No treatment-related deaths occurred.

“This population, enriched for patients with high risk features, showed remarkable response rates to R-BAC,” the investigators wrote. “The treatment had acceptable toxicity, maintained efficacy at attenuated doses, and was used successfully as a bridge to ASCT in over 20% of patients.”

The investigators suggested that R-BAC should be considered a new standard of care in the United Kingdom for bendamustine-naive patients who are unable to be enrolled in clinical trials. “The high response rate makes it particularly appealing for patients considered candidates for consolidation ASCT,” they wrote.

In an interview, Dr. Rule added perspective to these findings.

“There’s been an obsession with venetoclax, that that’s the answer, but it really isn’t,” Dr. Rule said. “So people are looking for a new drug. I guess what I do differently to most people is I use CHOP frontline rather than bendamustine. To me, that’s the best way of sequencing the therapies, whereas if you use [bendamustine and rituximab] up front, which a lot of people do, particularly in the [United] States, your R-BAC might not be so effective.”

However, Dr. Rule said that first-line therapies appear to have minimal impact on R-BAC efficacy. “Even if you’ve had bendamustine, even if you’ve had high-dose cytarabine, even if you’ve had an allogeneic stem cell transplant, [R-BAC] still works,” he said.

Where patients have issues with tolerability, Dr. Rule noted that dose reductions are possible without sacrificing efficacy.

He offered an example of such a scenario. “My oldest patient was about 80 with blastoid disease, relapsing,” Dr. Rule said. “After ibrutinib, I gave him just a single dose of bendamustine at 70 mg, a single dose of cytarabine at 500 mg, just 1 day, and he had that six times, probably 3 weeks apart. He’s been in complete remission for over a year.”

With data on 30 patients collected, Dr. Rule said that he and his colleagues plan to present more extensive findings at the European Hematology Association Congress, held June 13-16 in Amsterdam.

The investigators reported having no conflicts of interest.
 

High-cost hospital stays among elderly patients with cancer are associated with major procedures, more comorbid conditions, hematologic cancer, and metastatic cancer, according to a retrospective analysis of more than 570,000 inpatient visits.

Patients involved in the top 10% most expensive cancer-related hospital visits were more likely to have five or more comorbidities, or receive chemotherapy, reported lead author Jaqueline Avila, PhD candidate at the University of Texas Medical Branch in Galveston, and her colleagues.

“A small fraction (approximately 10%) of patients account for more than half of the overall health care costs incurred annually,” the investigators wrote. The report is in the Journal of Oncology Practice.

“[S]imilar to the general population, a small population of patients with cancer (the top 5% to 10% of patients with highest costs) accounts for more than 80% of the total cancer costs,” the investigators wrote. “However, we lack a detailed understanding of the characteristics of these high-cost and high-risk elderly patients with cancer.”

To gain insight, the investigators analyzed 574,367 cancer-related inpatient visits of patients aged 65 years or older, using data from the 2014 National Inpatient Sample. Visits were divided based on cost, with the top 10% most expensive visits in one group (n = 57,437) and the lower 90% of visits in another group (n = 516,930). The investigators then compared these groups based on a variety of patient factor covariates, including race, sex, age, type of cancer, comorbidities, treatments received, and hospital characteristics, such as private or public ownership and location.

The overall median cost of the top 10% of inpatient visits was $38,194 (interquartile range, $31,405-$51,802), compared with $8,257 in the lower-cost group (interquartile range, $5,032-$13,335). This was partly attributed to comorbidities. In the high-cost group, 38.4% of patients had five or more comorbidities, compared with 26.2% in the lower-cost group (P less than .001).

Procedures also factored into cost. The high-cost group had more procedures than did the lower-cost group (mean, 5.48 vs. 2.36; P less than .001), and expensive stays more often entailed major procedures (67.1% vs. 24.3%; P less than .001). Hematologic cancer and metastatic cancer were also more common in the high-cost group than in the lower-cost group, with rates of 23.5% versus 14.6% and 16.5% versus 11.8%, respectively. Among all cancer types, lymphoma, leukemia, and myeloma were the most expensive. The investigators noted that 97.9% of stem-cell or bone marrow transplants were received by patients with hematologic cancer.

Cost did not increase directly with age, as patients aged 65-84 years were more likely to have high-cost inpatient visits than were those who were aged 85 years or older.

The investigators suggested that complications of chronic diseases were likely at the root of this difference, particularly among patients in the 65- to 72-year range. “The difference in costs could also be because caregivers and clinicians may choose to provide only necessary and often less intensive procedures and care to the oldest patients,” the investigators wrote.

A variety of other factors were associated with high-cost visits, although to a lesser degree, including male sex, treatment at a metropolitan teaching hospital, higher median household income, radiation therapy, and large bed size.

The investigators stated that more research is needed to determine relationships between costs and medical necessity, and to develop strategies for reducing costs.

“Although we evaluated the drivers of hospital costs, we could not assess whether additional costs incurred by the high-cost group were medically necessary or could be prevented or whether these excess costs resulted in better outcomes,” the investigators wrote. “Additional research is needed to measure outcomes such as survival and quality of life in this high-cost group and also evaluate whether the excess cost is spent on medically necessary services.

“Future studies should address how implementation of models such as the integrative care model and hospice care may affect the distribution of high-cost and low-cost visits,” the investigators suggested.

Novartis funded the study. Dr. Chavez-MacGregor reported financial relationships with Pfizer and Genentech.

SOURCE: Avila et al. JOP. 2019 Apr 4. doi:10.1200/JOP.18.00706.

High-cost hospital stays among elderly patients with cancer are associated with major procedures, more comorbid conditions, hematologic cancer, and metastatic cancer, according to a retrospective analysis of more than 570,000 inpatient visits.

Patients involved in the top 10% most expensive cancer-related hospital visits were more likely to have five or more comorbidities, or receive chemotherapy, reported lead author Jaqueline Avila, PhD candidate at the University of Texas Medical Branch in Galveston, and her colleagues.

“A small fraction (approximately 10%) of patients account for more than half of the overall health care costs incurred annually,” the investigators wrote. The report is in the Journal of Oncology Practice.

“[S]imilar to the general population, a small population of patients with cancer (the top 5% to 10% of patients with highest costs) accounts for more than 80% of the total cancer costs,” the investigators wrote. “However, we lack a detailed understanding of the characteristics of these high-cost and high-risk elderly patients with cancer.”

To gain insight, the investigators analyzed 574,367 cancer-related inpatient visits of patients aged 65 years or older, using data from the 2014 National Inpatient Sample. Visits were divided based on cost, with the top 10% most expensive visits in one group (n = 57,437) and the lower 90% of visits in another group (n = 516,930). The investigators then compared these groups based on a variety of patient factor covariates, including race, sex, age, type of cancer, comorbidities, treatments received, and hospital characteristics, such as private or public ownership and location.

The overall median cost of the top 10% of inpatient visits was $38,194 (interquartile range, $31,405-$51,802), compared with $8,257 in the lower-cost group (interquartile range, $5,032-$13,335). This was partly attributed to comorbidities. In the high-cost group, 38.4% of patients had five or more comorbidities, compared with 26.2% in the lower-cost group (P less than .001).

Procedures also factored into cost. The high-cost group had more procedures than did the lower-cost group (mean, 5.48 vs. 2.36; P less than .001), and expensive stays more often entailed major procedures (67.1% vs. 24.3%; P less than .001). Hematologic cancer and metastatic cancer were also more common in the high-cost group than in the lower-cost group, with rates of 23.5% versus 14.6% and 16.5% versus 11.8%, respectively. Among all cancer types, lymphoma, leukemia, and myeloma were the most expensive. The investigators noted that 97.9% of stem-cell or bone marrow transplants were received by patients with hematologic cancer.

Cost did not increase directly with age, as patients aged 65-84 years were more likely to have high-cost inpatient visits than were those who were aged 85 years or older.

The investigators suggested that complications of chronic diseases were likely at the root of this difference, particularly among patients in the 65- to 72-year range. “The difference in costs could also be because caregivers and clinicians may choose to provide only necessary and often less intensive procedures and care to the oldest patients,” the investigators wrote.

A variety of other factors were associated with high-cost visits, although to a lesser degree, including male sex, treatment at a metropolitan teaching hospital, higher median household income, radiation therapy, and large bed size.

The investigators stated that more research is needed to determine relationships between costs and medical necessity, and to develop strategies for reducing costs.

“Although we evaluated the drivers of hospital costs, we could not assess whether additional costs incurred by the high-cost group were medically necessary or could be prevented or whether these excess costs resulted in better outcomes,” the investigators wrote. “Additional research is needed to measure outcomes such as survival and quality of life in this high-cost group and also evaluate whether the excess cost is spent on medically necessary services.

“Future studies should address how implementation of models such as the integrative care model and hospice care may affect the distribution of high-cost and low-cost visits,” the investigators suggested.

Novartis funded the study. Dr. Chavez-MacGregor reported financial relationships with Pfizer and Genentech.

SOURCE: Avila et al. JOP. 2019 Apr 4. doi:10.1200/JOP.18.00706.

High-cost hospital stays among elderly patients with cancer are associated with major procedures, more comorbid conditions, hematologic cancer, and metastatic cancer, according to a retrospective analysis of more than 570,000 inpatient visits.

Patients involved in the top 10% most expensive cancer-related hospital visits were more likely to have five or more comorbidities, or receive chemotherapy, reported lead author Jaqueline Avila, PhD candidate at the University of Texas Medical Branch in Galveston, and her colleagues.

“A small fraction (approximately 10%) of patients account for more than half of the overall health care costs incurred annually,” the investigators wrote. The report is in the Journal of Oncology Practice.

“[S]imilar to the general population, a small population of patients with cancer (the top 5% to 10% of patients with highest costs) accounts for more than 80% of the total cancer costs,” the investigators wrote. “However, we lack a detailed understanding of the characteristics of these high-cost and high-risk elderly patients with cancer.”

To gain insight, the investigators analyzed 574,367 cancer-related inpatient visits of patients aged 65 years or older, using data from the 2014 National Inpatient Sample. Visits were divided based on cost, with the top 10% most expensive visits in one group (n = 57,437) and the lower 90% of visits in another group (n = 516,930). The investigators then compared these groups based on a variety of patient factor covariates, including race, sex, age, type of cancer, comorbidities, treatments received, and hospital characteristics, such as private or public ownership and location.

The overall median cost of the top 10% of inpatient visits was $38,194 (interquartile range, $31,405-$51,802), compared with $8,257 in the lower-cost group (interquartile range, $5,032-$13,335). This was partly attributed to comorbidities. In the high-cost group, 38.4% of patients had five or more comorbidities, compared with 26.2% in the lower-cost group (P less than .001).

Procedures also factored into cost. The high-cost group had more procedures than did the lower-cost group (mean, 5.48 vs. 2.36; P less than .001), and expensive stays more often entailed major procedures (67.1% vs. 24.3%; P less than .001). Hematologic cancer and metastatic cancer were also more common in the high-cost group than in the lower-cost group, with rates of 23.5% versus 14.6% and 16.5% versus 11.8%, respectively. Among all cancer types, lymphoma, leukemia, and myeloma were the most expensive. The investigators noted that 97.9% of stem-cell or bone marrow transplants were received by patients with hematologic cancer.

Cost did not increase directly with age, as patients aged 65-84 years were more likely to have high-cost inpatient visits than were those who were aged 85 years or older.

The investigators suggested that complications of chronic diseases were likely at the root of this difference, particularly among patients in the 65- to 72-year range. “The difference in costs could also be because caregivers and clinicians may choose to provide only necessary and often less intensive procedures and care to the oldest patients,” the investigators wrote.

A variety of other factors were associated with high-cost visits, although to a lesser degree, including male sex, treatment at a metropolitan teaching hospital, higher median household income, radiation therapy, and large bed size.

The investigators stated that more research is needed to determine relationships between costs and medical necessity, and to develop strategies for reducing costs.

“Although we evaluated the drivers of hospital costs, we could not assess whether additional costs incurred by the high-cost group were medically necessary or could be prevented or whether these excess costs resulted in better outcomes,” the investigators wrote. “Additional research is needed to measure outcomes such as survival and quality of life in this high-cost group and also evaluate whether the excess cost is spent on medically necessary services.

“Future studies should address how implementation of models such as the integrative care model and hospice care may affect the distribution of high-cost and low-cost visits,” the investigators suggested.

Novartis funded the study. Dr. Chavez-MacGregor reported financial relationships with Pfizer and Genentech.

SOURCE: Avila et al. JOP. 2019 Apr 4. doi:10.1200/JOP.18.00706.

Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.

Will Pass/MDedge News

Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).

Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”

This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.

“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.

In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.

The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.

About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).

Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.

Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.

Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.

Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.

“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”

When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.

However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.

“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.

The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.

SOURCE: Cook G et al. BSH 2019, Abstract OR-018.

Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.

Will Pass/MDedge News

Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).

Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”

This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.

“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.

In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.

The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.

About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).

Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.

Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.

Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.

Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.

“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”

When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.

However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.

“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.

The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.

SOURCE: Cook G et al. BSH 2019, Abstract OR-018.

Glasgow – Patients with relapsed or refractory multiple myeloma (RRMM) who were treated with a combination of the oral protease inhibitor ixazomib with lenalidomide and dexamethasone (IRd) in routine clinical practice had similar responses to clinical trial patients, according to a global observational study.

Will Pass/MDedge News

Real-world progression-free survival (PFS) and overall response (OR) rates closely approximated data from the TOURMALINE‑MM1 trial, reported lead author Gordon Cook, MB ChB, PhD, clinical director of hematology at the University of Leeds (England).

Tolerability appeared slightly higher in routine clinical practice, and in agreement with previous real-world studies for RRMM, patients who received IRd in earlier lines of therapy had better outcomes than did those who received IRd in later lines of therapy. “The translation of clinical trial data into the real world is really important because we practice in the real world,” Dr. Cook said at the annual meeting of the British Society for Haematology. “We know that trials are really important for establishing efficacy and safety of drugs so they can get licensed and market access, but [clinical trials] often don’t tell us about the true effectiveness of the drugs and tolerability because the populations in trials are often different from [patients in] the real world.”

This situation leads to an evidence gap, which the present trial, dubbed INSIGHT MM aims to fill. INSIGHT is the largest global, prospective, observational trial for multiple myeloma conducted to date, with ongoing enrollment of about 4,200 patients from 15 countries with newly diagnosed or refractory/relapsed multiple myeloma. Dr. Cook estimated that recruitment would be complete by June of 2019.

“The aim of [INSIGHT MM] is to evaluate real-world treatment and outcomes [in multiple myeloma] over 5 years and beyond,” Dr. Cook said.

In combination with interim data from INSIGHT MM (n = 50), Dr. Cook reported patient outcomes from the Czech Registry of Monoclonal Gammopathies (n = 113), a similar database. Unlike INSIGHT MM, which includes patients treated with between one and three prior lines of therapy, the Czech registry does not cap the number of prior therapies. Overall, in the data presented by Dr. Cook, nine countries were represented; about 90% of which were European, although approximately 10% of patients were treated in the United States and about 1% were treated in Taiwan.

The median age of diagnosis was 67 years, with about 14% of patients over the age of 75 years. Median time from diagnosis to initiation of IRd was about 3.5 years (42.6 months), at which point 71% of patients had an Eastern Cooperative Oncology Group performance status of at least 1.

About two-thirds of the patients (65%) had IgG multiple myeloma, and 14% had extramedullary disease. The most common prior therapy was bortezomib (89%), followed by transplant (61%), thalidomide (42%), lenalidomide (21%), carfilzomib (11%), daratumumab (3%), and pomalidomide (2%).

Half of the patients received IRd as second-line therapy, while the other half received the treatment third-line (30%), or fourth-line or later (20%). Median duration of therapy was just over 1 year (14 months), with 62% of patients still receiving therapy at data cutoff.

Dr. Cook cautioned that with a median follow-up of 9.3 months, data are still immature. However, the results so far suggest strong similarities in tolerability and efficacy when comparing real-world and clinical trial administration of IRd.

Routine clinical use was associated with an overall response rate of 74%, compared with 78% in the TOURMALINE‑MM1 trial. Again, showing high similarity, median PFS rates were 20.9 months and 20.6 months for the present data set and the TOURMALINE‑MM1 trial, respectively.

Just 4% of patients permanently discontinued ixazomib in the real-world study, compared with 17% in the clinical trial, suggesting that IRd may be better tolerated in routine clinical practice than the trial data indicated.

“IRd is effective in this setting,” Dr. Cook said. “Bear in mind that patients in the real-world database were further down the line in terms of the treatment pathway, they had prior heavier exposure to bortezomib and lenalidomide, and their performance status was slightly less impressive than it was in [TOURMALINE‑MM1]; therefore, to see this level of response in the real world is very pleasing.”

When asked by an attendee if clinical trials should push for inclusion of patients more representative of real-world populations, Dr. Cook said no. “I think the way we conduct phase 3 clinical trials, in particular, has to be the way it is in order for us to ensure that we can actually get the absolute efficacy and the safety, and that has to be done by a refined population, I’m afraid,” he said.

However, Dr. Cook supported efforts to improve reliability of data for clinicians at the time of drug licensing.

“We should be running real-world exposure in parallel with phase 3 studies, which is harder to do but just requires a bit of imagination,” Dr. Cook said.

The study was funded by Takeda. The investigators reported financial relationships with Takeda and other companies.

SOURCE: Cook G et al. BSH 2019, Abstract OR-018.

GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.

Will Pass/MDedge News

A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.

Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.

“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.

The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.

Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.

Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.

“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”

Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.

Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.

“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”

Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.

“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.

Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”

The study was sponsored by NHS England. The investigators reported having no conflicts of interest.

SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.

GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.

Will Pass/MDedge News

A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.

Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.

“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.

The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.

Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.

Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.

“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”

Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.

Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.

“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”

Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.

“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.

Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”

The study was sponsored by NHS England. The investigators reported having no conflicts of interest.

SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.

GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.

Will Pass/MDedge News

A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.

Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.

“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.

The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.

Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.

Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.

“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”

Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.

Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.

“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”

Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.

“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.

Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”

The study was sponsored by NHS England. The investigators reported having no conflicts of interest.

SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.

For patients with endometrial cancer at high risk of progression, receiving a combination of taxane and platinum chemotherapy after surgery offers similar efficacy and tolerability as doxorubicin and cisplatin, the standard therapy, according to a recent phase 3 trial.

Progression-free and overall survival rates were similar across treatment types, reported lead author Hiroyuki Nomura, MD, of Keio University, Tokyo, and his colleagues. The findings maintain doxorubicin/cisplatin as standard therapy; however, taxane/platinum chemotherapy could be a possible alternative for some patients because of similar efficacy and tolerability with a distinct toxicity profile.

“Establishment of evidence and validation of the optimal postoperative adjuvant chemotherapy regimen for endometrial cancer are important issues,” the investigators wrote in JAMA Oncology.

The multicenter, open-label study involved 788 patients with endometrial cancer at risk of progression, based on histologic findings. Eligibility required that patients have a residual tumor of at least 2 cm without extension beyond the abdominal cavity. Patients were randomly grouped into one of three treatment groups: doxorubicin/cisplatin, paclitaxel/carboplatin, or docetaxel/cisplatin. If tolerated, six 3-week cycles were given. The median follow-up period was 7 years. The primary and secondary endpoints were 5-year progression free survival and overall survival, respectively.

Survival rates were statistically similar between groups. The 5-year progression-free survival rate was 73.3% for doxorubicin/cisplatin, 73.9% for paclitaxel/carboplatin, and 79.0% for docetaxel/cisplatin (P = .12); the 5-year overall survival rate was 82.7% for doxorubicin/cisplatin, 86.1% for paclitaxel/carboplatin, and 88.1% for docetaxel/cisplatin (P = .67). Tolerability was also comparable, with a small range of discontinuation rates across treatment types, from 20.2% to 25.5% (P = .14).

“Although the superiority of docetaxel plus cisplatin and paclitaxel plus carboplatin over doxorubicin plus cisplatin was not demonstrated, we found that the three regimens were comparable in therapeutic effect,” the investigators concluded. “[C]onsidering efficacy and tolerability, taxane plus platinum regimens may be an alternative to treatment with doxorubicin plus cisplatin.”

The study was funded by a Health Labour Sciences Research Grant with nonspecific funding from AstraZeneca, Eisai, Bristol-Myers Squibb, and others. The investigators reported financial relationships with Chugai, Sanofi, Takeda, AbbVie, and others.

SOURCE: Nomura H et al. JAMA Oncol. 2019 Mar 21. doi: 10.1001/jamaoncol.2019.0001.

For patients with endometrial cancer at high risk of progression, receiving a combination of taxane and platinum chemotherapy after surgery offers similar efficacy and tolerability as doxorubicin and cisplatin, the standard therapy, according to a recent phase 3 trial.

Progression-free and overall survival rates were similar across treatment types, reported lead author Hiroyuki Nomura, MD, of Keio University, Tokyo, and his colleagues. The findings maintain doxorubicin/cisplatin as standard therapy; however, taxane/platinum chemotherapy could be a possible alternative for some patients because of similar efficacy and tolerability with a distinct toxicity profile.

“Establishment of evidence and validation of the optimal postoperative adjuvant chemotherapy regimen for endometrial cancer are important issues,” the investigators wrote in JAMA Oncology.

The multicenter, open-label study involved 788 patients with endometrial cancer at risk of progression, based on histologic findings. Eligibility required that patients have a residual tumor of at least 2 cm without extension beyond the abdominal cavity. Patients were randomly grouped into one of three treatment groups: doxorubicin/cisplatin, paclitaxel/carboplatin, or docetaxel/cisplatin. If tolerated, six 3-week cycles were given. The median follow-up period was 7 years. The primary and secondary endpoints were 5-year progression free survival and overall survival, respectively.

Survival rates were statistically similar between groups. The 5-year progression-free survival rate was 73.3% for doxorubicin/cisplatin, 73.9% for paclitaxel/carboplatin, and 79.0% for docetaxel/cisplatin (P = .12); the 5-year overall survival rate was 82.7% for doxorubicin/cisplatin, 86.1% for paclitaxel/carboplatin, and 88.1% for docetaxel/cisplatin (P = .67). Tolerability was also comparable, with a small range of discontinuation rates across treatment types, from 20.2% to 25.5% (P = .14).

“Although the superiority of docetaxel plus cisplatin and paclitaxel plus carboplatin over doxorubicin plus cisplatin was not demonstrated, we found that the three regimens were comparable in therapeutic effect,” the investigators concluded. “[C]onsidering efficacy and tolerability, taxane plus platinum regimens may be an alternative to treatment with doxorubicin plus cisplatin.”

The study was funded by a Health Labour Sciences Research Grant with nonspecific funding from AstraZeneca, Eisai, Bristol-Myers Squibb, and others. The investigators reported financial relationships with Chugai, Sanofi, Takeda, AbbVie, and others.

SOURCE: Nomura H et al. JAMA Oncol. 2019 Mar 21. doi: 10.1001/jamaoncol.2019.0001.

For patients with endometrial cancer at high risk of progression, receiving a combination of taxane and platinum chemotherapy after surgery offers similar efficacy and tolerability as doxorubicin and cisplatin, the standard therapy, according to a recent phase 3 trial.

Progression-free and overall survival rates were similar across treatment types, reported lead author Hiroyuki Nomura, MD, of Keio University, Tokyo, and his colleagues. The findings maintain doxorubicin/cisplatin as standard therapy; however, taxane/platinum chemotherapy could be a possible alternative for some patients because of similar efficacy and tolerability with a distinct toxicity profile.

“Establishment of evidence and validation of the optimal postoperative adjuvant chemotherapy regimen for endometrial cancer are important issues,” the investigators wrote in JAMA Oncology.

The multicenter, open-label study involved 788 patients with endometrial cancer at risk of progression, based on histologic findings. Eligibility required that patients have a residual tumor of at least 2 cm without extension beyond the abdominal cavity. Patients were randomly grouped into one of three treatment groups: doxorubicin/cisplatin, paclitaxel/carboplatin, or docetaxel/cisplatin. If tolerated, six 3-week cycles were given. The median follow-up period was 7 years. The primary and secondary endpoints were 5-year progression free survival and overall survival, respectively.

Survival rates were statistically similar between groups. The 5-year progression-free survival rate was 73.3% for doxorubicin/cisplatin, 73.9% for paclitaxel/carboplatin, and 79.0% for docetaxel/cisplatin (P = .12); the 5-year overall survival rate was 82.7% for doxorubicin/cisplatin, 86.1% for paclitaxel/carboplatin, and 88.1% for docetaxel/cisplatin (P = .67). Tolerability was also comparable, with a small range of discontinuation rates across treatment types, from 20.2% to 25.5% (P = .14).

“Although the superiority of docetaxel plus cisplatin and paclitaxel plus carboplatin over doxorubicin plus cisplatin was not demonstrated, we found that the three regimens were comparable in therapeutic effect,” the investigators concluded. “[C]onsidering efficacy and tolerability, taxane plus platinum regimens may be an alternative to treatment with doxorubicin plus cisplatin.”

The study was funded by a Health Labour Sciences Research Grant with nonspecific funding from AstraZeneca, Eisai, Bristol-Myers Squibb, and others. The investigators reported financial relationships with Chugai, Sanofi, Takeda, AbbVie, and others.

SOURCE: Nomura H et al. JAMA Oncol. 2019 Mar 21. doi: 10.1001/jamaoncol.2019.0001.

For patients with chronic hepatitis B (HBV), an aspirin a day could keep hepatocellular carcinoma (HCC) away, according to a cohort study of more than 10,000 patients in Taiwan.

jimdeli/Fotolia

Sixteen years of data showed that daily aspirin therapy reduced the risk of HBV-related HCC by 29%, reported lead author Teng-Yu Lee, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and his colleagues. Analysis also showed that antiviral nucleos(t)ide analogue therapy and statin use were independently associated with reduced risk of HCC, whereas older age, cirrhosis, and male sex increased risk.

“Therapy with [nucleos(t)ide analogues] is associated with reductions in HCC risk, but the risk is not erased,” the investigators wrote in JAMA Internal Medicine. “Therefore, using only [nucleos(t)ide analogue] therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers, so another effective way of reducing HCC risk needs to be developed.”

Previous studies have shown that aspirin can reduce the risk of colorectal cancer; however, data supporting aspirin for HCC prevention are limited to a few animal models and human studies, the latter of which are statistically unreliable.

“Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC,” the investigators wrote.

They screened 204,507 patients with HBV included in the Taiwanese National Health Insurance Research Database (NHIRD) between 1997 and 2012, first excluding any with confounding conditions, such as hepatitis C infection or alcoholic liver disease. Next, 2,123 patients were identified who had taken aspirin for 90 days or longer. Finally, these cases were randomly matched with 8,492 control patients with HBV who had never received antiplatelet therapy. The main measured outcome was diagnosis with HCC. Patients were followed until this diagnosis was made, death occurred, or the end of the study period.

Analysis showed that most patients were male (72.4%) and took aspirin for about 4 years, usually prescribed for cardiovascular disease risk factors. Almost all patients in the treatment group (98%) received an aspirin dose of 100 mg or less.

After 5 years, the cumulative incidence of HCC in the aspirin group was 5.20% versus 7.87% in the control group (P less than .001). Multivariable analysis revealed that daily aspirin was associated with a significant risk reduction of 29% (HR 0.71; P less than .001), as were nucleos(t)ide analogues and statins, which lowered risk by 46% and 38%, respectively. In contrast, risk increased with older age at the rate of 1% per year, male sex carried an additional risk of 75%, and liver cirrhosis was associated with a 2.89-fold risk increase.

“In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with [chronic hepatitis B],” the investigators wrote. “Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.”

The investigators described several mechanisms that may have contribute to the possible risk reduction provided by aspirin. For one, aspirin inhibits platelet activation, which is associated with development of HBV-related liver disease. Additional benefit may come from induction of HCC cell apoptosis, control of tumor growth, reduced liver fibrosis, and increased liver regeneration, all of which have been associated with aspirin in rodent models.

“Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth,” the investigators wrote, suggesting that aspirin-related reductions in inflammation could also explain reduced neoplastic activity.

To assess for increased risk of peptic ulcers secondary to aspirin, the investigators performed a subanalysis of peptic ulcer bleeding. These results showed that rates of peptic ulcer bleeding, at around 5%-6%, were similar between the aspirin group and the control group. Among other variables, cirrhosis didn’t significantly affect rates of peptic ulcer bleeding, and aspirin users had similar rates of peptic ulcer bleeding regardless of HBV status. Because of the study design, however, the investigators cautioned that these analyses could underestimate ulcer risk because patients who could not tolerate aspirin for at least 90 days were excluded from the study.

Although statins stood out as another possible risk reducer, the investigators noted that “randomized clinical trials are required to confirm the chemopreventive effect of statins.”

Similarly, the investigators suggested that a prospective trial is needed before aspirin can be adopted as an HCC preventive.

The study was funded by the Ministry of Science and Technology, National Health Research Institutes, and Taichung (Taiwan) Veterans General Hospital, Taiwan. One author reported financial compensation from Gilead and Bristol-Myers Squibb.

SOURCE: Lee T-Y et al. JAMA Intern Med. 2019 Mar 18. doi:10.1001/jamainternmed.2018.8342.

For patients with chronic hepatitis B (HBV), an aspirin a day could keep hepatocellular carcinoma (HCC) away, according to a cohort study of more than 10,000 patients in Taiwan.

jimdeli/Fotolia

Sixteen years of data showed that daily aspirin therapy reduced the risk of HBV-related HCC by 29%, reported lead author Teng-Yu Lee, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and his colleagues. Analysis also showed that antiviral nucleos(t)ide analogue therapy and statin use were independently associated with reduced risk of HCC, whereas older age, cirrhosis, and male sex increased risk.

“Therapy with [nucleos(t)ide analogues] is associated with reductions in HCC risk, but the risk is not erased,” the investigators wrote in JAMA Internal Medicine. “Therefore, using only [nucleos(t)ide analogue] therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers, so another effective way of reducing HCC risk needs to be developed.”

Previous studies have shown that aspirin can reduce the risk of colorectal cancer; however, data supporting aspirin for HCC prevention are limited to a few animal models and human studies, the latter of which are statistically unreliable.

“Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC,” the investigators wrote.

They screened 204,507 patients with HBV included in the Taiwanese National Health Insurance Research Database (NHIRD) between 1997 and 2012, first excluding any with confounding conditions, such as hepatitis C infection or alcoholic liver disease. Next, 2,123 patients were identified who had taken aspirin for 90 days or longer. Finally, these cases were randomly matched with 8,492 control patients with HBV who had never received antiplatelet therapy. The main measured outcome was diagnosis with HCC. Patients were followed until this diagnosis was made, death occurred, or the end of the study period.

Analysis showed that most patients were male (72.4%) and took aspirin for about 4 years, usually prescribed for cardiovascular disease risk factors. Almost all patients in the treatment group (98%) received an aspirin dose of 100 mg or less.

After 5 years, the cumulative incidence of HCC in the aspirin group was 5.20% versus 7.87% in the control group (P less than .001). Multivariable analysis revealed that daily aspirin was associated with a significant risk reduction of 29% (HR 0.71; P less than .001), as were nucleos(t)ide analogues and statins, which lowered risk by 46% and 38%, respectively. In contrast, risk increased with older age at the rate of 1% per year, male sex carried an additional risk of 75%, and liver cirrhosis was associated with a 2.89-fold risk increase.

“In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with [chronic hepatitis B],” the investigators wrote. “Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.”

The investigators described several mechanisms that may have contribute to the possible risk reduction provided by aspirin. For one, aspirin inhibits platelet activation, which is associated with development of HBV-related liver disease. Additional benefit may come from induction of HCC cell apoptosis, control of tumor growth, reduced liver fibrosis, and increased liver regeneration, all of which have been associated with aspirin in rodent models.

“Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth,” the investigators wrote, suggesting that aspirin-related reductions in inflammation could also explain reduced neoplastic activity.

To assess for increased risk of peptic ulcers secondary to aspirin, the investigators performed a subanalysis of peptic ulcer bleeding. These results showed that rates of peptic ulcer bleeding, at around 5%-6%, were similar between the aspirin group and the control group. Among other variables, cirrhosis didn’t significantly affect rates of peptic ulcer bleeding, and aspirin users had similar rates of peptic ulcer bleeding regardless of HBV status. Because of the study design, however, the investigators cautioned that these analyses could underestimate ulcer risk because patients who could not tolerate aspirin for at least 90 days were excluded from the study.

Although statins stood out as another possible risk reducer, the investigators noted that “randomized clinical trials are required to confirm the chemopreventive effect of statins.”

Similarly, the investigators suggested that a prospective trial is needed before aspirin can be adopted as an HCC preventive.

The study was funded by the Ministry of Science and Technology, National Health Research Institutes, and Taichung (Taiwan) Veterans General Hospital, Taiwan. One author reported financial compensation from Gilead and Bristol-Myers Squibb.

SOURCE: Lee T-Y et al. JAMA Intern Med. 2019 Mar 18. doi:10.1001/jamainternmed.2018.8342.

For patients with chronic hepatitis B (HBV), an aspirin a day could keep hepatocellular carcinoma (HCC) away, according to a cohort study of more than 10,000 patients in Taiwan.

jimdeli/Fotolia

Sixteen years of data showed that daily aspirin therapy reduced the risk of HBV-related HCC by 29%, reported lead author Teng-Yu Lee, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and his colleagues. Analysis also showed that antiviral nucleos(t)ide analogue therapy and statin use were independently associated with reduced risk of HCC, whereas older age, cirrhosis, and male sex increased risk.

“Therapy with [nucleos(t)ide analogues] is associated with reductions in HCC risk, but the risk is not erased,” the investigators wrote in JAMA Internal Medicine. “Therefore, using only [nucleos(t)ide analogue] therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers, so another effective way of reducing HCC risk needs to be developed.”

Previous studies have shown that aspirin can reduce the risk of colorectal cancer; however, data supporting aspirin for HCC prevention are limited to a few animal models and human studies, the latter of which are statistically unreliable.

“Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC,” the investigators wrote.

They screened 204,507 patients with HBV included in the Taiwanese National Health Insurance Research Database (NHIRD) between 1997 and 2012, first excluding any with confounding conditions, such as hepatitis C infection or alcoholic liver disease. Next, 2,123 patients were identified who had taken aspirin for 90 days or longer. Finally, these cases were randomly matched with 8,492 control patients with HBV who had never received antiplatelet therapy. The main measured outcome was diagnosis with HCC. Patients were followed until this diagnosis was made, death occurred, or the end of the study period.

Analysis showed that most patients were male (72.4%) and took aspirin for about 4 years, usually prescribed for cardiovascular disease risk factors. Almost all patients in the treatment group (98%) received an aspirin dose of 100 mg or less.

After 5 years, the cumulative incidence of HCC in the aspirin group was 5.20% versus 7.87% in the control group (P less than .001). Multivariable analysis revealed that daily aspirin was associated with a significant risk reduction of 29% (HR 0.71; P less than .001), as were nucleos(t)ide analogues and statins, which lowered risk by 46% and 38%, respectively. In contrast, risk increased with older age at the rate of 1% per year, male sex carried an additional risk of 75%, and liver cirrhosis was associated with a 2.89-fold risk increase.

“In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with [chronic hepatitis B],” the investigators wrote. “Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.”

The investigators described several mechanisms that may have contribute to the possible risk reduction provided by aspirin. For one, aspirin inhibits platelet activation, which is associated with development of HBV-related liver disease. Additional benefit may come from induction of HCC cell apoptosis, control of tumor growth, reduced liver fibrosis, and increased liver regeneration, all of which have been associated with aspirin in rodent models.

“Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth,” the investigators wrote, suggesting that aspirin-related reductions in inflammation could also explain reduced neoplastic activity.

To assess for increased risk of peptic ulcers secondary to aspirin, the investigators performed a subanalysis of peptic ulcer bleeding. These results showed that rates of peptic ulcer bleeding, at around 5%-6%, were similar between the aspirin group and the control group. Among other variables, cirrhosis didn’t significantly affect rates of peptic ulcer bleeding, and aspirin users had similar rates of peptic ulcer bleeding regardless of HBV status. Because of the study design, however, the investigators cautioned that these analyses could underestimate ulcer risk because patients who could not tolerate aspirin for at least 90 days were excluded from the study.

Although statins stood out as another possible risk reducer, the investigators noted that “randomized clinical trials are required to confirm the chemopreventive effect of statins.”

Similarly, the investigators suggested that a prospective trial is needed before aspirin can be adopted as an HCC preventive.

The study was funded by the Ministry of Science and Technology, National Health Research Institutes, and Taichung (Taiwan) Veterans General Hospital, Taiwan. One author reported financial compensation from Gilead and Bristol-Myers Squibb.

SOURCE: Lee T-Y et al. JAMA Intern Med. 2019 Mar 18. doi:10.1001/jamainternmed.2018.8342.

Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

Ingram Publishing/Thinkstock

Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses,” the investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid ‘misuse and abuse’ as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

Ingram Publishing/Thinkstock

Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses,” the investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid ‘misuse and abuse’ as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

Many clinicians are prescribing the gabapentinoid drugs pregabalin (Lyrica) and gabapentin (Neurontin) for off-label treatment of pain, despite a lack of supporting data or approval from the Food and Drug Administration, according to investigators.

Over the past 15 years, use of gabapentinoids has tripled, a level of growth that cannot be explained by prescriptions for approved indications, reported coauthors Christopher W. Goodman, MD, and Allan S. Brett, MD, of the University of South Carolina, Columbia. Instead, clinicians are turning to gabapentinoids, partly as an option to substitute for opioids, which now have greater prescribing restrictions as a result of the current opioid crisis.

Ingram Publishing/Thinkstock

Although clinicians may cite guidelines that support off-label use of gabapentinoids for pain, the investigators warned that many of these recommendations stand on shaky ground.

“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses,” the investigators wrote in a clinical review published online March 25 in JAMA Internal Medicine.

The investigators narrowed down 677 publications to 84 papers describing the use of gabapentinoids for outpatient noncancer pain syndromes for which they are not FDA approved; 54 for gabapentin and 30 for pregabalin. In the domain of analgesia, both agents are currently FDA-approved for postherpetic neuralgia, while pregabalin is additionally approved for pain associated with fibromyalgia and neuropathic pain from diabetic neuropathy and spinal cord injury. Indications in reviewed studies ranged broadly, from conditions somewhat related to those currently approved, such as unspecified neuropathy, to dissimilar conditions, such as chronic pancreatitis and burn injury.

The investigators summarized findings from randomized clinical trials while using case studies to illustrate potential problems with off-label use. In addition, they reviewed the history of gabapentinoids and sources of recommendations for off-label use, such as guidelines and previous review articles.

Six major findings were reported: (1) evidence supporting gabapentin for diabetic neuropathy pain is “mixed at best”; (2) evidence supporting gabapentin for nondiabetic neuropathies is very limited; (3) evidence does not support gabapentinoids for radiculopathy or low back pain; (4) gabapentin has minimal benefit for fibromyalgia pain, based on minimal evidence; (5) evidence does not support gabapentinoids for acute herpes zoster pain; and (6) in almost all studies for other painful indications, gabapentinoids were ineffective or “associated with small analgesic effects that were statistically significant but of questionable clinical importance.”

Case studies complemented this overview, highlighting related clinical dilemmas that the investigators encounter “repeatedly” during inpatient and outpatient care. Along with off-label use, such as gabapentinoid prescriptions for acute sciatica, the investigators reported cases in which neuropathy was diagnosed in place of nonspecific lower body pain to facilitate gabapentin prescription. They also described apparent disregard for risks of polypharmacy in prescriptions for elderly patients and rote use of gabapentinoids in patients with diabetic neuropathy who did not have sufficient discomfort to warrant prescription.

The investigators also cited a number of problems with the language of reviews and guidelines involving gabapentinoids.

“The wording in many guidelines and review articles reinforces an inflated view of gabapentinoid effectiveness or fails to distinguish carefully between evidence-based and non–evidence-based recommendations,” they wrote, adding that clinicians may have misconceptions about neuropathic pain. “One unintended effect of the broad definition [of neuropathic pain] might be to create a mistaken perception that an effective drug for one type of neuropathic pain is effective for all neuropathic pain, regardless of underlying etiology or mechanism,” the investigators suggested.

Another facet of prescribing behavior could be explained in economic terms. Pregabalin, sold under the brand name Lyrica, is considerably more expensive than gabapentin; however, the investigators warned that the similarity of these agents does not equate with interchangeability, noting differences in bioavailability and rate of absorption.

“Unfortunately, published direct comparisons between the 2 drugs in double-blind studies of patients with chronic noncancer pain are virtually nonexistent,” the investigators wrote.

In addition to questionable effectiveness of gabapentinoids for off-label chronic noncancer pain syndromes, Dr. Goodman and Dr. Brett noted that the drugs produce a “substantial incidence of dizziness, somnolence, and gait disturbance.”

They also described a new trend of gabapentinoid abuse and diversion, which may not be surprising, considering that gabapentinoids are reported to augment opioid-induced euphoria.

“Evidence of misuse of gabapentinoids is accumulating and likely related to the opioid epidemic. A recent review article reported an overall population prevalence of gabapentinoid ‘misuse and abuse’ as high as 1%, with substantially higher prevalence noted among patients with opioid use disorders,” the investigators wrote. “This trend is troubling, particularly because concomitant use of opioids and gabapentinoids is associated with increased odds of opioid-related death. Whether these concerns apply to patients receiving long-term prescribed opioid therapy is unclear.”

In the era of the opioid crisis, the investigators acknowledged that many clinicians have serious concerns about adequately treating chronic noncancer pain.

“Comprehensive management of pain in primary care settings is difficult. It requires time and resources that are frequently unavailable,” the investigators wrote. “Many patients with chronic pain have limited or no access to high-quality pain practices or to nonpharmacologic interventions, such as cognitive behavior therapy.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Goodman CW et al. JAMA Intern Med. 2019 Mar 25. doi: 10.1001/jamainternmed.2019.0086

For patients with primary central nervous system lymphoma (PCNSL), adding rituximab to combination high-dose methotrexate and temozolomide significantly boosted the 5-year overall survival rate, according to a retrospective study.

The triplet combination could be a safe and effective first-line option for patients with PCNSL, particularly the frail and elderly, who may have issues with toxicity when receiving current standard care, reported lead author Cui Chen, MD, of Sun Yat-Sen University Cancer Center in Guangzhou, China, and his colleagues.

“An increasing number of studies and meta‐analyses have investigated the effect of rituximab in PCNSL, indicating that rituximab can robustly enhance the response rate and possibly improve survival,” the investigators wrote in Cancer Medicine. “However, data regarding the addition of rituximab to [methotrexate and temozolomide] for PCNSL are limited, and no study has directly compared the efficacy of [rituximab/high-dose methotrexate/temozolomide] to that of [high-dose methotrexate/temozolomide].”

The study involved 62 patients with untreated PCNSL who were diagnosed between 2005 and 2015. Out of the 62 patients, 32 received rituximab/high-dose methotrexate/temozolomide (RMT) and 30 received high-dose methotrexate/temozolomide (MT). Patients received up to eight cycles of therapy, with discontinuation upon disease progression or toxicity.

The results showed that patients treated with RMT had significantly better outcomes than those who received MT, first marked by objective response rates, which were 93.7% for RMT and 69.0% for MT.

Survival rates also showed the advantage of rituximab. For the RMT group, 2-year and 5-year progression-free survival rates were 81.3% and 53.3%, respectively, compared with 46.5% and 29.1% for patients receiving MT.

Most importantly, rituximab boosted overall survival to a significant and notable extent, with higher rates at 2 years (82.3% vs. 65.7%) and 5 years (82.3% vs. 50.0%).

Efficacy did not diminish safety, as no significant differences in toxicity were found between treatment types. The most common grade 3-4 toxicities were hematologic; most commonly, this entailed neutropenia, which occurred in about one-quarter of patients.

“Given its outstanding efficacy and favorable toxicity, we consider RMT to be a feasible and safe therapeutic approach as a first‐line treatment for PCNSL. Moreover, RMT is an ideal regimen for elderly patients and frail populations who may not tolerate [whole‐brain radiation therapy] or [autologous stem‐cell transplantation],” the researchers wrote.

The study was funded by the Natural Science Foundation of Guangdong Province. The researchers reported having no conflicts of interest.

SOURCE: Chen C et al. Cancer Med. 2019 Mar 1. doi: 10.1002/cam4.1906.

For patients with primary central nervous system lymphoma (PCNSL), adding rituximab to combination high-dose methotrexate and temozolomide significantly boosted the 5-year overall survival rate, according to a retrospective study.

The triplet combination could be a safe and effective first-line option for patients with PCNSL, particularly the frail and elderly, who may have issues with toxicity when receiving current standard care, reported lead author Cui Chen, MD, of Sun Yat-Sen University Cancer Center in Guangzhou, China, and his colleagues.

“An increasing number of studies and meta‐analyses have investigated the effect of rituximab in PCNSL, indicating that rituximab can robustly enhance the response rate and possibly improve survival,” the investigators wrote in Cancer Medicine. “However, data regarding the addition of rituximab to [methotrexate and temozolomide] for PCNSL are limited, and no study has directly compared the efficacy of [rituximab/high-dose methotrexate/temozolomide] to that of [high-dose methotrexate/temozolomide].”

The study involved 62 patients with untreated PCNSL who were diagnosed between 2005 and 2015. Out of the 62 patients, 32 received rituximab/high-dose methotrexate/temozolomide (RMT) and 30 received high-dose methotrexate/temozolomide (MT). Patients received up to eight cycles of therapy, with discontinuation upon disease progression or toxicity.

The results showed that patients treated with RMT had significantly better outcomes than those who received MT, first marked by objective response rates, which were 93.7% for RMT and 69.0% for MT.

Survival rates also showed the advantage of rituximab. For the RMT group, 2-year and 5-year progression-free survival rates were 81.3% and 53.3%, respectively, compared with 46.5% and 29.1% for patients receiving MT.

Most importantly, rituximab boosted overall survival to a significant and notable extent, with higher rates at 2 years (82.3% vs. 65.7%) and 5 years (82.3% vs. 50.0%).

Efficacy did not diminish safety, as no significant differences in toxicity were found between treatment types. The most common grade 3-4 toxicities were hematologic; most commonly, this entailed neutropenia, which occurred in about one-quarter of patients.

“Given its outstanding efficacy and favorable toxicity, we consider RMT to be a feasible and safe therapeutic approach as a first‐line treatment for PCNSL. Moreover, RMT is an ideal regimen for elderly patients and frail populations who may not tolerate [whole‐brain radiation therapy] or [autologous stem‐cell transplantation],” the researchers wrote.

The study was funded by the Natural Science Foundation of Guangdong Province. The researchers reported having no conflicts of interest.

SOURCE: Chen C et al. Cancer Med. 2019 Mar 1. doi: 10.1002/cam4.1906.

For patients with primary central nervous system lymphoma (PCNSL), adding rituximab to combination high-dose methotrexate and temozolomide significantly boosted the 5-year overall survival rate, according to a retrospective study.

The triplet combination could be a safe and effective first-line option for patients with PCNSL, particularly the frail and elderly, who may have issues with toxicity when receiving current standard care, reported lead author Cui Chen, MD, of Sun Yat-Sen University Cancer Center in Guangzhou, China, and his colleagues.

“An increasing number of studies and meta‐analyses have investigated the effect of rituximab in PCNSL, indicating that rituximab can robustly enhance the response rate and possibly improve survival,” the investigators wrote in Cancer Medicine. “However, data regarding the addition of rituximab to [methotrexate and temozolomide] for PCNSL are limited, and no study has directly compared the efficacy of [rituximab/high-dose methotrexate/temozolomide] to that of [high-dose methotrexate/temozolomide].”

The study involved 62 patients with untreated PCNSL who were diagnosed between 2005 and 2015. Out of the 62 patients, 32 received rituximab/high-dose methotrexate/temozolomide (RMT) and 30 received high-dose methotrexate/temozolomide (MT). Patients received up to eight cycles of therapy, with discontinuation upon disease progression or toxicity.

The results showed that patients treated with RMT had significantly better outcomes than those who received MT, first marked by objective response rates, which were 93.7% for RMT and 69.0% for MT.

Survival rates also showed the advantage of rituximab. For the RMT group, 2-year and 5-year progression-free survival rates were 81.3% and 53.3%, respectively, compared with 46.5% and 29.1% for patients receiving MT.

Most importantly, rituximab boosted overall survival to a significant and notable extent, with higher rates at 2 years (82.3% vs. 65.7%) and 5 years (82.3% vs. 50.0%).

Efficacy did not diminish safety, as no significant differences in toxicity were found between treatment types. The most common grade 3-4 toxicities were hematologic; most commonly, this entailed neutropenia, which occurred in about one-quarter of patients.

“Given its outstanding efficacy and favorable toxicity, we consider RMT to be a feasible and safe therapeutic approach as a first‐line treatment for PCNSL. Moreover, RMT is an ideal regimen for elderly patients and frail populations who may not tolerate [whole‐brain radiation therapy] or [autologous stem‐cell transplantation],” the researchers wrote.

The study was funded by the Natural Science Foundation of Guangdong Province. The researchers reported having no conflicts of interest.

SOURCE: Chen C et al. Cancer Med. 2019 Mar 1. doi: 10.1002/cam4.1906.