Susan London

VANCOUVER, B.C. – When patients with poorly controlled type 1 diabetes all receive good training in self-management, pump therapy is not superior to insulin injections in terms of glycemic control, according to findings from the REPOSE trial.

But the two differ somewhat on other outcomes.

A total of 317 adult patients in the United Kingdom were studied. Among the majority with a hemoglobin A_1c level at baseline indicating poor control, the reduction at 24 months did not differ significantly between those assigned to insulin pumps and those assigned to multiple daily injection (MDI) therapy, investigators reported at the World Diabetes Congress.

However, pump therapy was associated with a greater improvement in certain measures of diabetes-specific quality of life, and MDI therapy was associated with a lower rate of diabetic ketoacidosis.

“We believe that these results support a care pathway for adults with type 1 diabetes that starts with structured training using MDI but with pumps offered later to those in whom the limitations of MDI interfere with effective self-management,” commented lead investigator Dr. Simon Heller, professor of clinical diabetes at the University of Sheffield (England).

“Structured training reduces the risk of severe hypoglycemia and leads to modest but importantly long-lasting benefits in HbA_1c, and should be delivered much more widely, even in the U.K.,” he added. “But there is also no doubt that further work is needed … to develop effective approaches to support people in achieving tighter glucose targets while we wait for the artificial pancreas to become generally available.”

In an interview, session moderator Dr. Remi Rabasa-Lhoret, an endocrinologist with the Montreal Diabetes Research Center, commented, “I am overall disappointed. I would say my internal bias was that there would be a larger benefit with the pump.”

The fact that the trial enrolled a relatively unselected population may have played a role, he suggested. In particular, the patients studied had very high HbA_1c levels at baseline, with a mean exceeding 9%, which in some countries would be a contraindication to getting a pump. Thus, they may have been unlikely to benefit even with good training.

“Another message is that maybe you need CGM [continuous glucose monitoring],” Dr. Rabasa-Lhoret added. “But then you are having huge cost issues and access issues to really benefit from the pump.”

Dr. Heller, in introducing the trial, noted that meta-analyses have suggested that pumps may have an edge over MDI when it comes to glycemic control. But “one of the limitations in the existing evidence is that people allocated to pumps have received more training and attention, compared to MDI, and very few trials have compared pumps to MDI with comparable training and insulin adjustment,” he noted.

To be eligible for the REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) trial, patients had to have had type 1 diabetes for at least 1 year. Also, they had to be willing to undertake flexible intensive insulin therapy with self-monitoring of blood glucose and carbohydrate counting, and had to have no clinical indication or strong preference for a pump.

The patients were randomized to MDI (using rapid and twice-daily long-acting insulin analogues) or to pumps that provided continuous subcutaneous infusion of insulin. All were given 38 hours of high-quality structured education through the Dose Adjustment for Normal Eating (DAFNE) program, a skills-based program in flexible intensive insulin therapy and self-management.

The results for the entire trial population showed that among the large majority with baseline HbA_1c levels of at least 7.5%, the mean change at 24 months was –0.64%.

In an intent-to-treat analysis, the mean change was –0.84% in the pump group and –0.42% in the MDI group. After adjustment, the difference between groups was not significant (–0.23%; P = .121).

In a per-protocol analysis, however, there was a difference between groups in favor of the pump (–0.84% vs. –0.32%; difference, –0.34%; P = .018).

“Importantly, HbA_1c remained well above recommended national and international targets,” Dr. Heller said, with only about a fifth of patients in each group achieving an HbA_1c of less than 7.5%.

The trial population as a whole had a reduction in the annual number of episodes of severe hypoglycemia per patient from 0.17 before baseline to 0.10 during the trial (incidence rate ratio, 0.46; P = .021). Again, there was no difference between groups.

The groups were also statistically indistinguishable with respect to diabetes-specific quality of life, general measures of well-being, anxiety and depression, and fear of hypoglycemia. But the pump group had greater improvements than the MDI group in scores for diabetes-specific diet restrictions (P = .004), daily hassles and function (P = .006), and treatment satisfaction (P less than .001).

The rates of serious adverse events were generally similar across the two groups, except for a higher rate of diabetic ketoacidosis with the pump (12.9% vs. 3.7%). “The difference was confined to the first year,” Dr. Heller noted. Most of the episodes were due to general infections (for example, urinary tract and upper respiratory tract infections), and the number was small among patients who adhered to sick day rules that had been covered in training.

He offered a parting message to physicians considering putting their patients on pumps: “Make sure they are up to self-managing their diabetes really actively, and if they are, absolutely. … I’m a passionate proponent of using technology for people who are up for it.”

Session attendee Dr. Irl B. Hirsch of the University of Washington, Seattle, said, “I’m very curious … about the frequency of home blood glucose monitoring, because that’s the key in my opinion for any insulin delivery – are they checking their blood sugars enough to make the appropriate adjustments? Was there more testing in one group than the other?”

Those data were obtained from patients who reported them, but were otherwise not systematically collected, Dr. Heller said.

Dr. Heller disclosed that he receives consulting fees/honoraria from Eli Lilly, Novo Nordisk, Sanofi-Aventis, Takeda, MSD, AstraZeneca, Johnson and Johnson, and Boehringer Ingelheim, and that he has clinical trial affiliations with Medtronic, UK.

VANCOUVER, B.C. – When patients with poorly controlled type 1 diabetes all receive good training in self-management, pump therapy is not superior to insulin injections in terms of glycemic control, according to findings from the REPOSE trial.

But the two differ somewhat on other outcomes.

A total of 317 adult patients in the United Kingdom were studied. Among the majority with a hemoglobin A_1c level at baseline indicating poor control, the reduction at 24 months did not differ significantly between those assigned to insulin pumps and those assigned to multiple daily injection (MDI) therapy, investigators reported at the World Diabetes Congress.

However, pump therapy was associated with a greater improvement in certain measures of diabetes-specific quality of life, and MDI therapy was associated with a lower rate of diabetic ketoacidosis.

“We believe that these results support a care pathway for adults with type 1 diabetes that starts with structured training using MDI but with pumps offered later to those in whom the limitations of MDI interfere with effective self-management,” commented lead investigator Dr. Simon Heller, professor of clinical diabetes at the University of Sheffield (England).

“Structured training reduces the risk of severe hypoglycemia and leads to modest but importantly long-lasting benefits in HbA_1c, and should be delivered much more widely, even in the U.K.,” he added. “But there is also no doubt that further work is needed … to develop effective approaches to support people in achieving tighter glucose targets while we wait for the artificial pancreas to become generally available.”

In an interview, session moderator Dr. Remi Rabasa-Lhoret, an endocrinologist with the Montreal Diabetes Research Center, commented, “I am overall disappointed. I would say my internal bias was that there would be a larger benefit with the pump.”

The fact that the trial enrolled a relatively unselected population may have played a role, he suggested. In particular, the patients studied had very high HbA_1c levels at baseline, with a mean exceeding 9%, which in some countries would be a contraindication to getting a pump. Thus, they may have been unlikely to benefit even with good training.

“Another message is that maybe you need CGM [continuous glucose monitoring],” Dr. Rabasa-Lhoret added. “But then you are having huge cost issues and access issues to really benefit from the pump.”

Dr. Heller, in introducing the trial, noted that meta-analyses have suggested that pumps may have an edge over MDI when it comes to glycemic control. But “one of the limitations in the existing evidence is that people allocated to pumps have received more training and attention, compared to MDI, and very few trials have compared pumps to MDI with comparable training and insulin adjustment,” he noted.

To be eligible for the REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) trial, patients had to have had type 1 diabetes for at least 1 year. Also, they had to be willing to undertake flexible intensive insulin therapy with self-monitoring of blood glucose and carbohydrate counting, and had to have no clinical indication or strong preference for a pump.

The patients were randomized to MDI (using rapid and twice-daily long-acting insulin analogues) or to pumps that provided continuous subcutaneous infusion of insulin. All were given 38 hours of high-quality structured education through the Dose Adjustment for Normal Eating (DAFNE) program, a skills-based program in flexible intensive insulin therapy and self-management.

The results for the entire trial population showed that among the large majority with baseline HbA_1c levels of at least 7.5%, the mean change at 24 months was –0.64%.

In an intent-to-treat analysis, the mean change was –0.84% in the pump group and –0.42% in the MDI group. After adjustment, the difference between groups was not significant (–0.23%; P = .121).

In a per-protocol analysis, however, there was a difference between groups in favor of the pump (–0.84% vs. –0.32%; difference, –0.34%; P = .018).

“Importantly, HbA_1c remained well above recommended national and international targets,” Dr. Heller said, with only about a fifth of patients in each group achieving an HbA_1c of less than 7.5%.

The trial population as a whole had a reduction in the annual number of episodes of severe hypoglycemia per patient from 0.17 before baseline to 0.10 during the trial (incidence rate ratio, 0.46; P = .021). Again, there was no difference between groups.

The groups were also statistically indistinguishable with respect to diabetes-specific quality of life, general measures of well-being, anxiety and depression, and fear of hypoglycemia. But the pump group had greater improvements than the MDI group in scores for diabetes-specific diet restrictions (P = .004), daily hassles and function (P = .006), and treatment satisfaction (P less than .001).

The rates of serious adverse events were generally similar across the two groups, except for a higher rate of diabetic ketoacidosis with the pump (12.9% vs. 3.7%). “The difference was confined to the first year,” Dr. Heller noted. Most of the episodes were due to general infections (for example, urinary tract and upper respiratory tract infections), and the number was small among patients who adhered to sick day rules that had been covered in training.

He offered a parting message to physicians considering putting their patients on pumps: “Make sure they are up to self-managing their diabetes really actively, and if they are, absolutely. … I’m a passionate proponent of using technology for people who are up for it.”

Session attendee Dr. Irl B. Hirsch of the University of Washington, Seattle, said, “I’m very curious … about the frequency of home blood glucose monitoring, because that’s the key in my opinion for any insulin delivery – are they checking their blood sugars enough to make the appropriate adjustments? Was there more testing in one group than the other?”

Those data were obtained from patients who reported them, but were otherwise not systematically collected, Dr. Heller said.

Dr. Heller disclosed that he receives consulting fees/honoraria from Eli Lilly, Novo Nordisk, Sanofi-Aventis, Takeda, MSD, AstraZeneca, Johnson and Johnson, and Boehringer Ingelheim, and that he has clinical trial affiliations with Medtronic, UK.

VANCOUVER, B.C. – When patients with poorly controlled type 1 diabetes all receive good training in self-management, pump therapy is not superior to insulin injections in terms of glycemic control, according to findings from the REPOSE trial.

But the two differ somewhat on other outcomes.

A total of 317 adult patients in the United Kingdom were studied. Among the majority with a hemoglobin A_1c level at baseline indicating poor control, the reduction at 24 months did not differ significantly between those assigned to insulin pumps and those assigned to multiple daily injection (MDI) therapy, investigators reported at the World Diabetes Congress.

However, pump therapy was associated with a greater improvement in certain measures of diabetes-specific quality of life, and MDI therapy was associated with a lower rate of diabetic ketoacidosis.

“We believe that these results support a care pathway for adults with type 1 diabetes that starts with structured training using MDI but with pumps offered later to those in whom the limitations of MDI interfere with effective self-management,” commented lead investigator Dr. Simon Heller, professor of clinical diabetes at the University of Sheffield (England).

“Structured training reduces the risk of severe hypoglycemia and leads to modest but importantly long-lasting benefits in HbA_1c, and should be delivered much more widely, even in the U.K.,” he added. “But there is also no doubt that further work is needed … to develop effective approaches to support people in achieving tighter glucose targets while we wait for the artificial pancreas to become generally available.”

In an interview, session moderator Dr. Remi Rabasa-Lhoret, an endocrinologist with the Montreal Diabetes Research Center, commented, “I am overall disappointed. I would say my internal bias was that there would be a larger benefit with the pump.”

The fact that the trial enrolled a relatively unselected population may have played a role, he suggested. In particular, the patients studied had very high HbA_1c levels at baseline, with a mean exceeding 9%, which in some countries would be a contraindication to getting a pump. Thus, they may have been unlikely to benefit even with good training.

“Another message is that maybe you need CGM [continuous glucose monitoring],” Dr. Rabasa-Lhoret added. “But then you are having huge cost issues and access issues to really benefit from the pump.”

Dr. Heller, in introducing the trial, noted that meta-analyses have suggested that pumps may have an edge over MDI when it comes to glycemic control. But “one of the limitations in the existing evidence is that people allocated to pumps have received more training and attention, compared to MDI, and very few trials have compared pumps to MDI with comparable training and insulin adjustment,” he noted.

To be eligible for the REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) trial, patients had to have had type 1 diabetes for at least 1 year. Also, they had to be willing to undertake flexible intensive insulin therapy with self-monitoring of blood glucose and carbohydrate counting, and had to have no clinical indication or strong preference for a pump.

The patients were randomized to MDI (using rapid and twice-daily long-acting insulin analogues) or to pumps that provided continuous subcutaneous infusion of insulin. All were given 38 hours of high-quality structured education through the Dose Adjustment for Normal Eating (DAFNE) program, a skills-based program in flexible intensive insulin therapy and self-management.

The results for the entire trial population showed that among the large majority with baseline HbA_1c levels of at least 7.5%, the mean change at 24 months was –0.64%.

In an intent-to-treat analysis, the mean change was –0.84% in the pump group and –0.42% in the MDI group. After adjustment, the difference between groups was not significant (–0.23%; P = .121).

In a per-protocol analysis, however, there was a difference between groups in favor of the pump (–0.84% vs. –0.32%; difference, –0.34%; P = .018).

“Importantly, HbA_1c remained well above recommended national and international targets,” Dr. Heller said, with only about a fifth of patients in each group achieving an HbA_1c of less than 7.5%.

The trial population as a whole had a reduction in the annual number of episodes of severe hypoglycemia per patient from 0.17 before baseline to 0.10 during the trial (incidence rate ratio, 0.46; P = .021). Again, there was no difference between groups.

The groups were also statistically indistinguishable with respect to diabetes-specific quality of life, general measures of well-being, anxiety and depression, and fear of hypoglycemia. But the pump group had greater improvements than the MDI group in scores for diabetes-specific diet restrictions (P = .004), daily hassles and function (P = .006), and treatment satisfaction (P less than .001).

The rates of serious adverse events were generally similar across the two groups, except for a higher rate of diabetic ketoacidosis with the pump (12.9% vs. 3.7%). “The difference was confined to the first year,” Dr. Heller noted. Most of the episodes were due to general infections (for example, urinary tract and upper respiratory tract infections), and the number was small among patients who adhered to sick day rules that had been covered in training.

He offered a parting message to physicians considering putting their patients on pumps: “Make sure they are up to self-managing their diabetes really actively, and if they are, absolutely. … I’m a passionate proponent of using technology for people who are up for it.”

Session attendee Dr. Irl B. Hirsch of the University of Washington, Seattle, said, “I’m very curious … about the frequency of home blood glucose monitoring, because that’s the key in my opinion for any insulin delivery – are they checking their blood sugars enough to make the appropriate adjustments? Was there more testing in one group than the other?”

Those data were obtained from patients who reported them, but were otherwise not systematically collected, Dr. Heller said.

Dr. Heller disclosed that he receives consulting fees/honoraria from Eli Lilly, Novo Nordisk, Sanofi-Aventis, Takeda, MSD, AstraZeneca, Johnson and Johnson, and Boehringer Ingelheim, and that he has clinical trial affiliations with Medtronic, UK.

VANCOUVER, B.C. – When patients with poorly controlled type 1 diabetes all receive good training in self-management, pump therapy is not superior to insulin injections in terms of glycemic control, according to findings from the REPOSE trial.

But the two differ somewhat on other outcomes.

A total of 317 adult patients in the United Kingdom were studied. Among the majority with a hemoglobin A_1c level at baseline indicating poor control, the reduction at 24 months did not differ significantly between those assigned to insulin pumps and those assigned to multiple daily injection (MDI) therapy, investigators reported at the World Diabetes Congress.

However, pump therapy was associated with a greater improvement in certain measures of diabetes-specific quality of life, and MDI therapy was associated with a lower rate of diabetic ketoacidosis.

“We believe that these results support a care pathway for adults with type 1 diabetes that starts with structured training using MDI but with pumps offered later to those in whom the limitations of MDI interfere with effective self-management,” commented lead investigator Dr. Simon Heller, professor of clinical diabetes at the University of Sheffield (England).

“Structured training reduces the risk of severe hypoglycemia and leads to modest but importantly long-lasting benefits in HbA_1c, and should be delivered much more widely, even in the U.K.,” he added. “But there is also no doubt that further work is needed … to develop effective approaches to support people in achieving tighter glucose targets while we wait for the artificial pancreas to become generally available.”

In an interview, session moderator Dr. Remi Rabasa-Lhoret, an endocrinologist with the Montreal Diabetes Research Center, commented, “I am overall disappointed. I would say my internal bias was that there would be a larger benefit with the pump.”

The fact that the trial enrolled a relatively unselected population may have played a role, he suggested. In particular, the patients studied had very high HbA_1c levels at baseline, with a mean exceeding 9%, which in some countries would be a contraindication to getting a pump. Thus, they may have been unlikely to benefit even with good training.

“Another message is that maybe you need CGM [continuous glucose monitoring],” Dr. Rabasa-Lhoret added. “But then you are having huge cost issues and access issues to really benefit from the pump.”

Dr. Heller, in introducing the trial, noted that meta-analyses have suggested that pumps may have an edge over MDI when it comes to glycemic control. But “one of the limitations in the existing evidence is that people allocated to pumps have received more training and attention, compared to MDI, and very few trials have compared pumps to MDI with comparable training and insulin adjustment,” he noted.

To be eligible for the REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) trial, patients had to have had type 1 diabetes for at least 1 year. Also, they had to be willing to undertake flexible intensive insulin therapy with self-monitoring of blood glucose and carbohydrate counting, and had to have no clinical indication or strong preference for a pump.

The patients were randomized to MDI (using rapid and twice-daily long-acting insulin analogues) or to pumps that provided continuous subcutaneous infusion of insulin. All were given 38 hours of high-quality structured education through the Dose Adjustment for Normal Eating (DAFNE) program, a skills-based program in flexible intensive insulin therapy and self-management.

The results for the entire trial population showed that among the large majority with baseline HbA_1c levels of at least 7.5%, the mean change at 24 months was –0.64%.

In an intent-to-treat analysis, the mean change was –0.84% in the pump group and –0.42% in the MDI group. After adjustment, the difference between groups was not significant (–0.23%; P = .121).

In a per-protocol analysis, however, there was a difference between groups in favor of the pump (–0.84% vs. –0.32%; difference, –0.34%; P = .018).

“Importantly, HbA_1c remained well above recommended national and international targets,” Dr. Heller said, with only about a fifth of patients in each group achieving an HbA_1c of less than 7.5%.

The trial population as a whole had a reduction in the annual number of episodes of severe hypoglycemia per patient from 0.17 before baseline to 0.10 during the trial (incidence rate ratio, 0.46; P = .021). Again, there was no difference between groups.

The groups were also statistically indistinguishable with respect to diabetes-specific quality of life, general measures of well-being, anxiety and depression, and fear of hypoglycemia. But the pump group had greater improvements than the MDI group in scores for diabetes-specific diet restrictions (P = .004), daily hassles and function (P = .006), and treatment satisfaction (P less than .001).

The rates of serious adverse events were generally similar across the two groups, except for a higher rate of diabetic ketoacidosis with the pump (12.9% vs. 3.7%). “The difference was confined to the first year,” Dr. Heller noted. Most of the episodes were due to general infections (for example, urinary tract and upper respiratory tract infections), and the number was small among patients who adhered to sick day rules that had been covered in training.

He offered a parting message to physicians considering putting their patients on pumps: “Make sure they are up to self-managing their diabetes really actively, and if they are, absolutely. … I’m a passionate proponent of using technology for people who are up for it.”

Session attendee Dr. Irl B. Hirsch of the University of Washington, Seattle, said, “I’m very curious … about the frequency of home blood glucose monitoring, because that’s the key in my opinion for any insulin delivery – are they checking their blood sugars enough to make the appropriate adjustments? Was there more testing in one group than the other?”

Those data were obtained from patients who reported them, but were otherwise not systematically collected, Dr. Heller said.

Dr. Heller disclosed that he receives consulting fees/honoraria from Eli Lilly, Novo Nordisk, Sanofi-Aventis, Takeda, MSD, AstraZeneca, Johnson and Johnson, and Boehringer Ingelheim, and that he has clinical trial affiliations with Medtronic, UK.

VANCOUVER, B.C. – When patients with poorly controlled type 1 diabetes all receive good training in self-management, pump therapy is not superior to insulin injections in terms of glycemic control, according to findings from the REPOSE trial.

But the two differ somewhat on other outcomes.

A total of 317 adult patients in the United Kingdom were studied. Among the majority with a hemoglobin A_1c level at baseline indicating poor control, the reduction at 24 months did not differ significantly between those assigned to insulin pumps and those assigned to multiple daily injection (MDI) therapy, investigators reported at the World Diabetes Congress.

However, pump therapy was associated with a greater improvement in certain measures of diabetes-specific quality of life, and MDI therapy was associated with a lower rate of diabetic ketoacidosis.

“We believe that these results support a care pathway for adults with type 1 diabetes that starts with structured training using MDI but with pumps offered later to those in whom the limitations of MDI interfere with effective self-management,” commented lead investigator Dr. Simon Heller, professor of clinical diabetes at the University of Sheffield (England).

“Structured training reduces the risk of severe hypoglycemia and leads to modest but importantly long-lasting benefits in HbA_1c, and should be delivered much more widely, even in the U.K.,” he added. “But there is also no doubt that further work is needed … to develop effective approaches to support people in achieving tighter glucose targets while we wait for the artificial pancreas to become generally available.”

In an interview, session moderator Dr. Remi Rabasa-Lhoret, an endocrinologist with the Montreal Diabetes Research Center, commented, “I am overall disappointed. I would say my internal bias was that there would be a larger benefit with the pump.”

The fact that the trial enrolled a relatively unselected population may have played a role, he suggested. In particular, the patients studied had very high HbA_1c levels at baseline, with a mean exceeding 9%, which in some countries would be a contraindication to getting a pump. Thus, they may have been unlikely to benefit even with good training.

“Another message is that maybe you need CGM [continuous glucose monitoring],” Dr. Rabasa-Lhoret added. “But then you are having huge cost issues and access issues to really benefit from the pump.”

Dr. Heller, in introducing the trial, noted that meta-analyses have suggested that pumps may have an edge over MDI when it comes to glycemic control. But “one of the limitations in the existing evidence is that people allocated to pumps have received more training and attention, compared to MDI, and very few trials have compared pumps to MDI with comparable training and insulin adjustment,” he noted.

To be eligible for the REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) trial, patients had to have had type 1 diabetes for at least 1 year. Also, they had to be willing to undertake flexible intensive insulin therapy with self-monitoring of blood glucose and carbohydrate counting, and had to have no clinical indication or strong preference for a pump.

The patients were randomized to MDI (using rapid and twice-daily long-acting insulin analogues) or to pumps that provided continuous subcutaneous infusion of insulin. All were given 38 hours of high-quality structured education through the Dose Adjustment for Normal Eating (DAFNE) program, a skills-based program in flexible intensive insulin therapy and self-management.

The results for the entire trial population showed that among the large majority with baseline HbA_1c levels of at least 7.5%, the mean change at 24 months was –0.64%.

In an intent-to-treat analysis, the mean change was –0.84% in the pump group and –0.42% in the MDI group. After adjustment, the difference between groups was not significant (–0.23%; P = .121).

In a per-protocol analysis, however, there was a difference between groups in favor of the pump (–0.84% vs. –0.32%; difference, –0.34%; P = .018).

“Importantly, HbA_1c remained well above recommended national and international targets,” Dr. Heller said, with only about a fifth of patients in each group achieving an HbA_1c of less than 7.5%.

The trial population as a whole had a reduction in the annual number of episodes of severe hypoglycemia per patient from 0.17 before baseline to 0.10 during the trial (incidence rate ratio, 0.46; P = .021). Again, there was no difference between groups.

The groups were also statistically indistinguishable with respect to diabetes-specific quality of life, general measures of well-being, anxiety and depression, and fear of hypoglycemia. But the pump group had greater improvements than the MDI group in scores for diabetes-specific diet restrictions (P = .004), daily hassles and function (P = .006), and treatment satisfaction (P less than .001).

The rates of serious adverse events were generally similar across the two groups, except for a higher rate of diabetic ketoacidosis with the pump (12.9% vs. 3.7%). “The difference was confined to the first year,” Dr. Heller noted. Most of the episodes were due to general infections (for example, urinary tract and upper respiratory tract infections), and the number was small among patients who adhered to sick day rules that had been covered in training.

He offered a parting message to physicians considering putting their patients on pumps: “Make sure they are up to self-managing their diabetes really actively, and if they are, absolutely. … I’m a passionate proponent of using technology for people who are up for it.”

Session attendee Dr. Irl B. Hirsch of the University of Washington, Seattle, said, “I’m very curious … about the frequency of home blood glucose monitoring, because that’s the key in my opinion for any insulin delivery – are they checking their blood sugars enough to make the appropriate adjustments? Was there more testing in one group than the other?”

Those data were obtained from patients who reported them, but were otherwise not systematically collected, Dr. Heller said.

Dr. Heller disclosed that he receives consulting fees/honoraria from Eli Lilly, Novo Nordisk, Sanofi-Aventis, Takeda, MSD, AstraZeneca, Johnson and Johnson, and Boehringer Ingelheim, and that he has clinical trial affiliations with Medtronic, UK.

VANCOUVER, B.C. – When patients with poorly controlled type 1 diabetes all receive good training in self-management, pump therapy is not superior to insulin injections in terms of glycemic control, according to findings from the REPOSE trial.

But the two differ somewhat on other outcomes.

A total of 317 adult patients in the United Kingdom were studied. Among the majority with a hemoglobin A_1c level at baseline indicating poor control, the reduction at 24 months did not differ significantly between those assigned to insulin pumps and those assigned to multiple daily injection (MDI) therapy, investigators reported at the World Diabetes Congress.

However, pump therapy was associated with a greater improvement in certain measures of diabetes-specific quality of life, and MDI therapy was associated with a lower rate of diabetic ketoacidosis.

“We believe that these results support a care pathway for adults with type 1 diabetes that starts with structured training using MDI but with pumps offered later to those in whom the limitations of MDI interfere with effective self-management,” commented lead investigator Dr. Simon Heller, professor of clinical diabetes at the University of Sheffield (England).

“Structured training reduces the risk of severe hypoglycemia and leads to modest but importantly long-lasting benefits in HbA_1c, and should be delivered much more widely, even in the U.K.,” he added. “But there is also no doubt that further work is needed … to develop effective approaches to support people in achieving tighter glucose targets while we wait for the artificial pancreas to become generally available.”

In an interview, session moderator Dr. Remi Rabasa-Lhoret, an endocrinologist with the Montreal Diabetes Research Center, commented, “I am overall disappointed. I would say my internal bias was that there would be a larger benefit with the pump.”

The fact that the trial enrolled a relatively unselected population may have played a role, he suggested. In particular, the patients studied had very high HbA_1c levels at baseline, with a mean exceeding 9%, which in some countries would be a contraindication to getting a pump. Thus, they may have been unlikely to benefit even with good training.

“Another message is that maybe you need CGM [continuous glucose monitoring],” Dr. Rabasa-Lhoret added. “But then you are having huge cost issues and access issues to really benefit from the pump.”

Dr. Heller, in introducing the trial, noted that meta-analyses have suggested that pumps may have an edge over MDI when it comes to glycemic control. But “one of the limitations in the existing evidence is that people allocated to pumps have received more training and attention, compared to MDI, and very few trials have compared pumps to MDI with comparable training and insulin adjustment,” he noted.

To be eligible for the REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) trial, patients had to have had type 1 diabetes for at least 1 year. Also, they had to be willing to undertake flexible intensive insulin therapy with self-monitoring of blood glucose and carbohydrate counting, and had to have no clinical indication or strong preference for a pump.

The patients were randomized to MDI (using rapid and twice-daily long-acting insulin analogues) or to pumps that provided continuous subcutaneous infusion of insulin. All were given 38 hours of high-quality structured education through the Dose Adjustment for Normal Eating (DAFNE) program, a skills-based program in flexible intensive insulin therapy and self-management.

The results for the entire trial population showed that among the large majority with baseline HbA_1c levels of at least 7.5%, the mean change at 24 months was –0.64%.

In an intent-to-treat analysis, the mean change was –0.84% in the pump group and –0.42% in the MDI group. After adjustment, the difference between groups was not significant (–0.23%; P = .121).

In a per-protocol analysis, however, there was a difference between groups in favor of the pump (–0.84% vs. –0.32%; difference, –0.34%; P = .018).

“Importantly, HbA_1c remained well above recommended national and international targets,” Dr. Heller said, with only about a fifth of patients in each group achieving an HbA_1c of less than 7.5%.

The trial population as a whole had a reduction in the annual number of episodes of severe hypoglycemia per patient from 0.17 before baseline to 0.10 during the trial (incidence rate ratio, 0.46; P = .021). Again, there was no difference between groups.

The groups were also statistically indistinguishable with respect to diabetes-specific quality of life, general measures of well-being, anxiety and depression, and fear of hypoglycemia. But the pump group had greater improvements than the MDI group in scores for diabetes-specific diet restrictions (P = .004), daily hassles and function (P = .006), and treatment satisfaction (P less than .001).

The rates of serious adverse events were generally similar across the two groups, except for a higher rate of diabetic ketoacidosis with the pump (12.9% vs. 3.7%). “The difference was confined to the first year,” Dr. Heller noted. Most of the episodes were due to general infections (for example, urinary tract and upper respiratory tract infections), and the number was small among patients who adhered to sick day rules that had been covered in training.

He offered a parting message to physicians considering putting their patients on pumps: “Make sure they are up to self-managing their diabetes really actively, and if they are, absolutely. … I’m a passionate proponent of using technology for people who are up for it.”

Session attendee Dr. Irl B. Hirsch of the University of Washington, Seattle, said, “I’m very curious … about the frequency of home blood glucose monitoring, because that’s the key in my opinion for any insulin delivery – are they checking their blood sugars enough to make the appropriate adjustments? Was there more testing in one group than the other?”

Those data were obtained from patients who reported them, but were otherwise not systematically collected, Dr. Heller said.

Dr. Heller disclosed that he receives consulting fees/honoraria from Eli Lilly, Novo Nordisk, Sanofi-Aventis, Takeda, MSD, AstraZeneca, Johnson and Johnson, and Boehringer Ingelheim, and that he has clinical trial affiliations with Medtronic, UK.

SAN ANTONIO – Adjuvant capecitabine improves outcomes in women with HER2-negative breast cancer who still have invasive disease after neoadjuvant chemotherapy, according to findings of the CREATE-X trial reported at the San Antonio Breast Cancer Symposium.

“Patients with pathologic residual invasive disease after neoadjuvant chemotherapy have a higher risk for relapse,” said presenting author Dr. Masakazu Toi, a professor at Kyoto University Hospital in Japan, and founder and senior director of the Japan Breast Cancer Research Group (JBCRG). But “it is unclear whether postoperative systemic chemotherapy following neoadjuvant chemotherapy is able to prolong survival.”

The phase III trial was conducted among 910 patients with early breast cancer in Japan and Korea who still had positive nodes or didn’t achieve a pathologic complete response after receipt of neoadjuvant chemotherapy that included an anthracycline, a taxane, or both. They were randomized to open-label adjuvant capecitabine (Xeloda) or no capecitabine, in addition to standard therapy.

Results of a preplanned 2-year interim analysis, reported in a session and related press briefing, showed that the risk of disease-free survival events was 30% lower and the risk of death was 40% lower among women given capecitabine than among counterparts not given the drug, prompting early stopping of the trial.

The disease-free survival results were similar in subgroup analyses. In particular, benefit was similar in patients with triple-negative disease, who historically haven’t fared well on this drug.

“The balance of benefit and toxicity would favor the use of capecitabine in [this] post–neoadjuvant chemotherapy situation, but prediction for therapeutic benefit needs to be investigated further,” Dr. Toi concluded. “The cost-effectiveness analysis will be carried out soon,” he added.

Press briefing moderator Dr. Virginia Kaklamani, codirector of the San Antonio Breast Cancer Symposium, as well as professor of medicine in the division of hematology/oncology at the University of Texas, San Antonio, and leader of the Breast Cancer Program, Cancer Therapy & Research Center there, wondered if the results are practice changing.

“On Monday morning, when I see a patient who has residual disease after neoadjuvant chemotherapy, what do I tell her?” she asked.

“I think we need to take care of the reimbursement issue,” Dr. Toi replied, referring to the current lack of U.S. Food and Drug Administration approval of capecitabine for this indication. “But personally, I would like to consider this treatment.”

In the session where the findings were presented, some attendees expressed skepticism about the observed benefit of capecitabine, given previous studies.

This benefit may have been due in part to the fact that in CREATE-X, capecitabine was given largely because it does not have cross-resistance with anthracyclines and taxanes, Dr. Toi speculated.

Attendee Dr. Steven Vogl, an oncologist at the Montefiore Medical Center in New York, proposed that the findings may have different implications for women with estrogen receptor–positive versus triple-negative disease, based on both their likelihood of pathologic complete response (pCR)and the prognostic impact of that response.

“I put it to you that really what this tells us is if we have a triple-negative patient who doesn’t achieve pCR after good neoadjuvant therapy, this [capecitabine] is probably a reasonable option, even though it’s quite toxic, and certainly should be explored further,” he said. “I’m not sure I would go home and treat my ER-positive patients who don’t get a pCR with capecitabine based on this study.”

In the trial, the 2-year disease-free survival rate – the trial’s primary endpoint – was 82.8% with capecitabine and 74.0% without it. The estimated 5-year rates were 74.1% and 67.7%, respectively (hazard ratio, 0.70; P = .005).

Furthermore, the 2-year overall survival rate was 94% with capecitabine and 89.2% without it. The estimated 5-year rates were 89.2% and 83.9%, respectively (HR, 0.60; P less than .01).

Patients in the capecitabine arm were more likely to experience grade 3 or worse neutropenia (7% vs. 2%) and diarrhea (3% vs. less than 1%). And 11% developed grade 3 hand-foot syndrome. However, these toxicities were manageable, according to the investigators.

Dr. Toi disclosed that he receives a research grant from Chugai Pharmaceutical Company. The trial was supported by a grant from Specified Nonprofit Corporation – Advanced Clinical Research Organization (ACRO) and other donations to the Japan Breast Cancer Research Group.

SAN ANTONIO – Adjuvant capecitabine improves outcomes in women with HER2-negative breast cancer who still have invasive disease after neoadjuvant chemotherapy, according to findings of the CREATE-X trial reported at the San Antonio Breast Cancer Symposium.

“Patients with pathologic residual invasive disease after neoadjuvant chemotherapy have a higher risk for relapse,” said presenting author Dr. Masakazu Toi, a professor at Kyoto University Hospital in Japan, and founder and senior director of the Japan Breast Cancer Research Group (JBCRG). But “it is unclear whether postoperative systemic chemotherapy following neoadjuvant chemotherapy is able to prolong survival.”

The phase III trial was conducted among 910 patients with early breast cancer in Japan and Korea who still had positive nodes or didn’t achieve a pathologic complete response after receipt of neoadjuvant chemotherapy that included an anthracycline, a taxane, or both. They were randomized to open-label adjuvant capecitabine (Xeloda) or no capecitabine, in addition to standard therapy.

Results of a preplanned 2-year interim analysis, reported in a session and related press briefing, showed that the risk of disease-free survival events was 30% lower and the risk of death was 40% lower among women given capecitabine than among counterparts not given the drug, prompting early stopping of the trial.

The disease-free survival results were similar in subgroup analyses. In particular, benefit was similar in patients with triple-negative disease, who historically haven’t fared well on this drug.

“The balance of benefit and toxicity would favor the use of capecitabine in [this] post–neoadjuvant chemotherapy situation, but prediction for therapeutic benefit needs to be investigated further,” Dr. Toi concluded. “The cost-effectiveness analysis will be carried out soon,” he added.

Press briefing moderator Dr. Virginia Kaklamani, codirector of the San Antonio Breast Cancer Symposium, as well as professor of medicine in the division of hematology/oncology at the University of Texas, San Antonio, and leader of the Breast Cancer Program, Cancer Therapy & Research Center there, wondered if the results are practice changing.

“On Monday morning, when I see a patient who has residual disease after neoadjuvant chemotherapy, what do I tell her?” she asked.

“I think we need to take care of the reimbursement issue,” Dr. Toi replied, referring to the current lack of U.S. Food and Drug Administration approval of capecitabine for this indication. “But personally, I would like to consider this treatment.”

In the session where the findings were presented, some attendees expressed skepticism about the observed benefit of capecitabine, given previous studies.

This benefit may have been due in part to the fact that in CREATE-X, capecitabine was given largely because it does not have cross-resistance with anthracyclines and taxanes, Dr. Toi speculated.

Attendee Dr. Steven Vogl, an oncologist at the Montefiore Medical Center in New York, proposed that the findings may have different implications for women with estrogen receptor–positive versus triple-negative disease, based on both their likelihood of pathologic complete response (pCR)and the prognostic impact of that response.

“I put it to you that really what this tells us is if we have a triple-negative patient who doesn’t achieve pCR after good neoadjuvant therapy, this [capecitabine] is probably a reasonable option, even though it’s quite toxic, and certainly should be explored further,” he said. “I’m not sure I would go home and treat my ER-positive patients who don’t get a pCR with capecitabine based on this study.”

In the trial, the 2-year disease-free survival rate – the trial’s primary endpoint – was 82.8% with capecitabine and 74.0% without it. The estimated 5-year rates were 74.1% and 67.7%, respectively (hazard ratio, 0.70; P = .005).

Furthermore, the 2-year overall survival rate was 94% with capecitabine and 89.2% without it. The estimated 5-year rates were 89.2% and 83.9%, respectively (HR, 0.60; P less than .01).

Patients in the capecitabine arm were more likely to experience grade 3 or worse neutropenia (7% vs. 2%) and diarrhea (3% vs. less than 1%). And 11% developed grade 3 hand-foot syndrome. However, these toxicities were manageable, according to the investigators.

Dr. Toi disclosed that he receives a research grant from Chugai Pharmaceutical Company. The trial was supported by a grant from Specified Nonprofit Corporation – Advanced Clinical Research Organization (ACRO) and other donations to the Japan Breast Cancer Research Group.

SAN ANTONIO – Adjuvant capecitabine improves outcomes in women with HER2-negative breast cancer who still have invasive disease after neoadjuvant chemotherapy, according to findings of the CREATE-X trial reported at the San Antonio Breast Cancer Symposium.

“Patients with pathologic residual invasive disease after neoadjuvant chemotherapy have a higher risk for relapse,” said presenting author Dr. Masakazu Toi, a professor at Kyoto University Hospital in Japan, and founder and senior director of the Japan Breast Cancer Research Group (JBCRG). But “it is unclear whether postoperative systemic chemotherapy following neoadjuvant chemotherapy is able to prolong survival.”

The phase III trial was conducted among 910 patients with early breast cancer in Japan and Korea who still had positive nodes or didn’t achieve a pathologic complete response after receipt of neoadjuvant chemotherapy that included an anthracycline, a taxane, or both. They were randomized to open-label adjuvant capecitabine (Xeloda) or no capecitabine, in addition to standard therapy.

Results of a preplanned 2-year interim analysis, reported in a session and related press briefing, showed that the risk of disease-free survival events was 30% lower and the risk of death was 40% lower among women given capecitabine than among counterparts not given the drug, prompting early stopping of the trial.

The disease-free survival results were similar in subgroup analyses. In particular, benefit was similar in patients with triple-negative disease, who historically haven’t fared well on this drug.

“The balance of benefit and toxicity would favor the use of capecitabine in [this] post–neoadjuvant chemotherapy situation, but prediction for therapeutic benefit needs to be investigated further,” Dr. Toi concluded. “The cost-effectiveness analysis will be carried out soon,” he added.

Press briefing moderator Dr. Virginia Kaklamani, codirector of the San Antonio Breast Cancer Symposium, as well as professor of medicine in the division of hematology/oncology at the University of Texas, San Antonio, and leader of the Breast Cancer Program, Cancer Therapy & Research Center there, wondered if the results are practice changing.

“On Monday morning, when I see a patient who has residual disease after neoadjuvant chemotherapy, what do I tell her?” she asked.

“I think we need to take care of the reimbursement issue,” Dr. Toi replied, referring to the current lack of U.S. Food and Drug Administration approval of capecitabine for this indication. “But personally, I would like to consider this treatment.”

In the session where the findings were presented, some attendees expressed skepticism about the observed benefit of capecitabine, given previous studies.

This benefit may have been due in part to the fact that in CREATE-X, capecitabine was given largely because it does not have cross-resistance with anthracyclines and taxanes, Dr. Toi speculated.

Attendee Dr. Steven Vogl, an oncologist at the Montefiore Medical Center in New York, proposed that the findings may have different implications for women with estrogen receptor–positive versus triple-negative disease, based on both their likelihood of pathologic complete response (pCR)and the prognostic impact of that response.

“I put it to you that really what this tells us is if we have a triple-negative patient who doesn’t achieve pCR after good neoadjuvant therapy, this [capecitabine] is probably a reasonable option, even though it’s quite toxic, and certainly should be explored further,” he said. “I’m not sure I would go home and treat my ER-positive patients who don’t get a pCR with capecitabine based on this study.”

In the trial, the 2-year disease-free survival rate – the trial’s primary endpoint – was 82.8% with capecitabine and 74.0% without it. The estimated 5-year rates were 74.1% and 67.7%, respectively (hazard ratio, 0.70; P = .005).

Furthermore, the 2-year overall survival rate was 94% with capecitabine and 89.2% without it. The estimated 5-year rates were 89.2% and 83.9%, respectively (HR, 0.60; P less than .01).

Patients in the capecitabine arm were more likely to experience grade 3 or worse neutropenia (7% vs. 2%) and diarrhea (3% vs. less than 1%). And 11% developed grade 3 hand-foot syndrome. However, these toxicities were manageable, according to the investigators.

Dr. Toi disclosed that he receives a research grant from Chugai Pharmaceutical Company. The trial was supported by a grant from Specified Nonprofit Corporation – Advanced Clinical Research Organization (ACRO) and other donations to the Japan Breast Cancer Research Group.

VANCOUVER, B.C. – Despite agreeing to use birth control and receiving frequent counseling about pregnancy avoidance, a sizable share of teens with type 2 diabetes mellitus become pregnant, and these pregnancies often have poor outcomes, researchers reported at the World Diabetes Congress.

The analysis was based on 452 female participants in the national Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, the largest trial in youth with this form of diabetes to date and one designed to have good representation of various racial/ethnic groups.

Overall, 10% of the girls became pregnant during a period of up to 6.5 years. The majority were not using contraception and did not recall the counseling. More than one-fourth of the pregnancies ended in fetal loss or stillbirth. And one-fifth of live-born infants had major congenital anomalies.

“We need to better understand the reasons for pregnancy in youth with type 2 diabetes and why, despite counseling, they become pregnant,” commented first author Dr. Kristen J. Nadeau of the division of pediatric endocrinology, department of pediatrics, University of Colorado, Aurora.

“Best practices for metabolically unhealthy pregnancy prevention in type 2 diabetic teens also requires further study,” she added. “Long-acting contraception, we think, currently is the best method and likely the way to go in these girls who are not retaining the education and [adhering to] the behaviors that we are hoping for.”

“This study is critically important and horribly depressing,” commented session comoderator Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, Washington, as well as chief scientific and medical officer of the American Diabetes Association, Alexandria, Va.

“It points out the difficulties of being a teenager and the even greater difficulties of being a teenager with a chronic disease,” he said in an interview, adding that there are no easy solutions.

“The combination of a teen pregnancy in someone with type 2 diabetes creates the perfect storm,” Dr. Nadeau noted. “Diabetes control is worse in adolescence than in any other time in the lifespan, and with increasing rates of type 2 diabetes in youth, increases in a teen pregnancy that are complicated by diabetes are anticipated,” she added.

At baseline, participants in TODAY were 10-17 years old, were overweight or obese, and had a diabetes duration of less than 2 years and a hemoglobin A_1c level of less than 8%. They were randomized to three treatment arms (metformin alone, metformin plus rosiglitazone, or metformin plus an intensive lifestyle program).

Consent for the trial required the use of a birth control method, including abstinence; in addition, every 2-3 months, the girls received diabetes education and counseling to defer pregnancy until their HbA_1c level fell below 6%. They also had regular pregnancy testing, and those with a positive result were taken off their trial medication and referred to a maternal-fetal medicine specialist.

The results reported at the meeting and simultaneously published in Diabetes Care (doi: 10.2337/dc15-1206) showed that 46 (10.2%) of the girls had 63 pregnancies. On average, they were 18 years old at the time of a first pregnancy.

Despite the counseling, only about 5% of those teens who became pregnant reported that they had been using contraception. Moreover, just 13% recalled the counseling.

The median body mass index closest to conception was 35.2 kg/m², and the median HbA_1c level was 7%. “Because of the fact that we were so heavily monitoring these girls, we had their HbA_1c under better control than is typical. In our typical clinic, the mean is more like 8.5%-9%,” Dr. Nadeau noted.

Relative to peers who did not become pregnant, those who did were significantly older, were less likely to be living with both parents or their mother, and had a lower household income.

Seven of the 63 pregnancies were electively terminated. Of the 53 remaining pregnancies with data, 12 ended in pregnancy loss and 2 ended in a stillbirth.

Among the 39 live-born infants, 6 were preterm and 8 had major congenital anomalies. And among the 37 with known birth weight, 10 were either small or large for gestational age.

Girls randomized to metformin plus rosiglitazone had a higher rate of term normal births than peers in the other arms (P = .027). “Of note, none of the participants reported taking the rosiglitazone after the pregnancy was discovered, as was per the study protocol,” Dr. Nadeau commented. In contrast, neither maternal body mass index nor – surprisingly – HbA_1c level was significantly associated with pregnancy outcome.

The rate of preterm birth observed in the teens studied was similar to what has been seen in adult women with diabetes, she noted. But the rate of major congenital anomalies was about four times higher.

“This potentially might be due to lower overall socioeconomic status of the girls in the TODAY study. Other reasons for the anomalies are uncertain, but might include metabolic control, smoking, or extreme obesity,” she said.

Dr. Nadeau disclosed that she had no relevant conflicts of interest.

VANCOUVER, B.C. – Despite agreeing to use birth control and receiving frequent counseling about pregnancy avoidance, a sizable share of teens with type 2 diabetes mellitus become pregnant, and these pregnancies often have poor outcomes, researchers reported at the World Diabetes Congress.

The analysis was based on 452 female participants in the national Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, the largest trial in youth with this form of diabetes to date and one designed to have good representation of various racial/ethnic groups.

Overall, 10% of the girls became pregnant during a period of up to 6.5 years. The majority were not using contraception and did not recall the counseling. More than one-fourth of the pregnancies ended in fetal loss or stillbirth. And one-fifth of live-born infants had major congenital anomalies.

“We need to better understand the reasons for pregnancy in youth with type 2 diabetes and why, despite counseling, they become pregnant,” commented first author Dr. Kristen J. Nadeau of the division of pediatric endocrinology, department of pediatrics, University of Colorado, Aurora.

“Best practices for metabolically unhealthy pregnancy prevention in type 2 diabetic teens also requires further study,” she added. “Long-acting contraception, we think, currently is the best method and likely the way to go in these girls who are not retaining the education and [adhering to] the behaviors that we are hoping for.”

“This study is critically important and horribly depressing,” commented session comoderator Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, Washington, as well as chief scientific and medical officer of the American Diabetes Association, Alexandria, Va.

“It points out the difficulties of being a teenager and the even greater difficulties of being a teenager with a chronic disease,” he said in an interview, adding that there are no easy solutions.

“The combination of a teen pregnancy in someone with type 2 diabetes creates the perfect storm,” Dr. Nadeau noted. “Diabetes control is worse in adolescence than in any other time in the lifespan, and with increasing rates of type 2 diabetes in youth, increases in a teen pregnancy that are complicated by diabetes are anticipated,” she added.

At baseline, participants in TODAY were 10-17 years old, were overweight or obese, and had a diabetes duration of less than 2 years and a hemoglobin A_1c level of less than 8%. They were randomized to three treatment arms (metformin alone, metformin plus rosiglitazone, or metformin plus an intensive lifestyle program).

Consent for the trial required the use of a birth control method, including abstinence; in addition, every 2-3 months, the girls received diabetes education and counseling to defer pregnancy until their HbA_1c level fell below 6%. They also had regular pregnancy testing, and those with a positive result were taken off their trial medication and referred to a maternal-fetal medicine specialist.

The results reported at the meeting and simultaneously published in Diabetes Care (doi: 10.2337/dc15-1206) showed that 46 (10.2%) of the girls had 63 pregnancies. On average, they were 18 years old at the time of a first pregnancy.

Despite the counseling, only about 5% of those teens who became pregnant reported that they had been using contraception. Moreover, just 13% recalled the counseling.

The median body mass index closest to conception was 35.2 kg/m², and the median HbA_1c level was 7%. “Because of the fact that we were so heavily monitoring these girls, we had their HbA_1c under better control than is typical. In our typical clinic, the mean is more like 8.5%-9%,” Dr. Nadeau noted.

Relative to peers who did not become pregnant, those who did were significantly older, were less likely to be living with both parents or their mother, and had a lower household income.

Seven of the 63 pregnancies were electively terminated. Of the 53 remaining pregnancies with data, 12 ended in pregnancy loss and 2 ended in a stillbirth.

Among the 39 live-born infants, 6 were preterm and 8 had major congenital anomalies. And among the 37 with known birth weight, 10 were either small or large for gestational age.

Girls randomized to metformin plus rosiglitazone had a higher rate of term normal births than peers in the other arms (P = .027). “Of note, none of the participants reported taking the rosiglitazone after the pregnancy was discovered, as was per the study protocol,” Dr. Nadeau commented. In contrast, neither maternal body mass index nor – surprisingly – HbA_1c level was significantly associated with pregnancy outcome.

The rate of preterm birth observed in the teens studied was similar to what has been seen in adult women with diabetes, she noted. But the rate of major congenital anomalies was about four times higher.

“This potentially might be due to lower overall socioeconomic status of the girls in the TODAY study. Other reasons for the anomalies are uncertain, but might include metabolic control, smoking, or extreme obesity,” she said.

Dr. Nadeau disclosed that she had no relevant conflicts of interest.

VANCOUVER, B.C. – Despite agreeing to use birth control and receiving frequent counseling about pregnancy avoidance, a sizable share of teens with type 2 diabetes mellitus become pregnant, and these pregnancies often have poor outcomes, researchers reported at the World Diabetes Congress.

The analysis was based on 452 female participants in the national Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, the largest trial in youth with this form of diabetes to date and one designed to have good representation of various racial/ethnic groups.

Overall, 10% of the girls became pregnant during a period of up to 6.5 years. The majority were not using contraception and did not recall the counseling. More than one-fourth of the pregnancies ended in fetal loss or stillbirth. And one-fifth of live-born infants had major congenital anomalies.

“We need to better understand the reasons for pregnancy in youth with type 2 diabetes and why, despite counseling, they become pregnant,” commented first author Dr. Kristen J. Nadeau of the division of pediatric endocrinology, department of pediatrics, University of Colorado, Aurora.

“Best practices for metabolically unhealthy pregnancy prevention in type 2 diabetic teens also requires further study,” she added. “Long-acting contraception, we think, currently is the best method and likely the way to go in these girls who are not retaining the education and [adhering to] the behaviors that we are hoping for.”

“This study is critically important and horribly depressing,” commented session comoderator Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, Washington, as well as chief scientific and medical officer of the American Diabetes Association, Alexandria, Va.

“It points out the difficulties of being a teenager and the even greater difficulties of being a teenager with a chronic disease,” he said in an interview, adding that there are no easy solutions.

“The combination of a teen pregnancy in someone with type 2 diabetes creates the perfect storm,” Dr. Nadeau noted. “Diabetes control is worse in adolescence than in any other time in the lifespan, and with increasing rates of type 2 diabetes in youth, increases in a teen pregnancy that are complicated by diabetes are anticipated,” she added.

At baseline, participants in TODAY were 10-17 years old, were overweight or obese, and had a diabetes duration of less than 2 years and a hemoglobin A_1c level of less than 8%. They were randomized to three treatment arms (metformin alone, metformin plus rosiglitazone, or metformin plus an intensive lifestyle program).

Consent for the trial required the use of a birth control method, including abstinence; in addition, every 2-3 months, the girls received diabetes education and counseling to defer pregnancy until their HbA_1c level fell below 6%. They also had regular pregnancy testing, and those with a positive result were taken off their trial medication and referred to a maternal-fetal medicine specialist.

The results reported at the meeting and simultaneously published in Diabetes Care (doi: 10.2337/dc15-1206) showed that 46 (10.2%) of the girls had 63 pregnancies. On average, they were 18 years old at the time of a first pregnancy.

Despite the counseling, only about 5% of those teens who became pregnant reported that they had been using contraception. Moreover, just 13% recalled the counseling.

The median body mass index closest to conception was 35.2 kg/m², and the median HbA_1c level was 7%. “Because of the fact that we were so heavily monitoring these girls, we had their HbA_1c under better control than is typical. In our typical clinic, the mean is more like 8.5%-9%,” Dr. Nadeau noted.

Relative to peers who did not become pregnant, those who did were significantly older, were less likely to be living with both parents or their mother, and had a lower household income.

Seven of the 63 pregnancies were electively terminated. Of the 53 remaining pregnancies with data, 12 ended in pregnancy loss and 2 ended in a stillbirth.

Among the 39 live-born infants, 6 were preterm and 8 had major congenital anomalies. And among the 37 with known birth weight, 10 were either small or large for gestational age.

Girls randomized to metformin plus rosiglitazone had a higher rate of term normal births than peers in the other arms (P = .027). “Of note, none of the participants reported taking the rosiglitazone after the pregnancy was discovered, as was per the study protocol,” Dr. Nadeau commented. In contrast, neither maternal body mass index nor – surprisingly – HbA_1c level was significantly associated with pregnancy outcome.

The rate of preterm birth observed in the teens studied was similar to what has been seen in adult women with diabetes, she noted. But the rate of major congenital anomalies was about four times higher.

“This potentially might be due to lower overall socioeconomic status of the girls in the TODAY study. Other reasons for the anomalies are uncertain, but might include metabolic control, smoking, or extreme obesity,” she said.

Dr. Nadeau disclosed that she had no relevant conflicts of interest.

VANCOUVER – Intensive glucose control needs to begin early in the course of kidney disease to have its greatest renal protective effect in patients with type 2 diabetes, suggests a study reported at the World Diabetes Congress.

The conclusions are based on long-term follow-up of patients with type 2 diabetes and high vascular risk who were treated on an international randomized trial for about 5 years with either intensive or standard glucose control.

Results for the 8,494 patients at a median total follow-up of nearly a decade showed that patients with lesser stages of chronic kidney disease (CKD) at the start of the study benefited more from intensive over standard glucose control in reducing the risk of onset of dialysis or renal transplantation, reported Dr. Sophia Zoungas.

Reassuringly, intensive glucose lowering was not associated with an increase in the risk of death or cardiovascular death, regardless of patients’ CKD stage at baseline. And the higher relative risk of severe hypoglycemia with the intensive strategy was likewise similar across baseline CKD stages.

“We think that the commencement of intensive glucose control is particularly important early in the disease process, and hopefully we can get in before the development of significant kidney disease,” said Dr. Zoungas, an endocrinologist with the Monash University School of Public Health and Preventive Medicine in Clayton, Australia.

“The lesser benefit in those with moderately reduced kidney function (CKD stage 3 or greater) may indicate that the glucose-independent mechanisms of renal progression may predominate in the later stages of the disease,” she speculated.

These new data are helpful for real-world clinical care, according to session co-moderator Dr. David A. D’Alessio, a professor of medicine and director of the division of endocrinology, metabolism, and nutrition at Duke University, Durham, N.C.

“I think this study was really important. It shows the strength of doing a good trial and then not stopping at 5 years, but continuing to collect data,” he said in an interview. “These studies end up being really useful to practitioners because we oftentimes see patients whom we’ve followed for up to 10 years.”

The patients studied had participated in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), which tested both intensive glucose control and blood pressure–lowering therapy. After the 5-year trial, patients returned to their usual practitioners’ care but had continued collection of data. The ADVANCE post-trial observational study (ADVANCE-ON) analyses were conducted after a median total follow-up of 9.9 years. Main findings were previously published (N Engl J Med. 2014;371:1392-406).

The greater reduction in hemoglobin A1c levels seen with intensive glucose control versus standard control on the trial was lost after the trial ended, Dr. Zoungas noted. “So if there was any effect in ADVANCE-ON, it would be attributable to the difference achieved during the in-trial period,” she said.

Compared with peers in the standard control group, patients in the intensive control group had a reduction in the risk of end-stage kidney disease during the entire follow-up (hazard ratio, 0.54) similar to that seen while they were on the trial (hazard ratio, 0.35).

In subgroup analyses, the lower the baseline stage of CKD, the greater the edge of intensive glucose control over standard glucose control for reducing the risk of end-stage kidney disease. The hazard ratio was 0.16 for patients with no CKD at baseline, 0.34 for those with stage 1 or 2, and 0.89 for patients with stage 3 or higher (P = .04). The number needed to treat for 5 years to prevent one case of end-stage kidney disease during the entire follow-up was 259, 109, and 393, respectively.

“What’s interesting to note here is that during the overall 9.9 years of follow-up, we have smaller numbers needed to treat for those with no evidence of CKD or early-stage CKD,” Dr. Zoungas said.

The investigators explored treatment impact on all-cause mortality and cardiovascular mortality according to baseline CKD stage, prompted by findings from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showing increased risks of these outcomes in patients with mild to moderate CKD at baseline who received intensive glucose control (Kidney Int. 2015;87:649-59).

ADVANCE-ON results, in contrast, showed no significant elevation in risk with intensive control, either while patients were on the trial or for the total 9.9 years of follow-up even in those at the more advanced stages of CKD, Dr. Zoungas said.

The relative risk of severe hypoglycemia was similarly elevated with intensive control, compared with standard control across CKD subgroups, although the absolute risk was higher for those with stage 3 or higher disease.

Dr. Zoungas disclosed that she receives honoraria from Servier for speaking about ADVANCE and ADVANCE-ON at scientific meetings, and that she is on the speakers bureau and advisory boards for and receives travel support from Merck Sharp & Dohme and AstraZeneca/Bristol-Myers Squibb. The study was funded in part by Servier.

VANCOUVER – Intensive glucose control needs to begin early in the course of kidney disease to have its greatest renal protective effect in patients with type 2 diabetes, suggests a study reported at the World Diabetes Congress.

The conclusions are based on long-term follow-up of patients with type 2 diabetes and high vascular risk who were treated on an international randomized trial for about 5 years with either intensive or standard glucose control.

Results for the 8,494 patients at a median total follow-up of nearly a decade showed that patients with lesser stages of chronic kidney disease (CKD) at the start of the study benefited more from intensive over standard glucose control in reducing the risk of onset of dialysis or renal transplantation, reported Dr. Sophia Zoungas.

Reassuringly, intensive glucose lowering was not associated with an increase in the risk of death or cardiovascular death, regardless of patients’ CKD stage at baseline. And the higher relative risk of severe hypoglycemia with the intensive strategy was likewise similar across baseline CKD stages.

“We think that the commencement of intensive glucose control is particularly important early in the disease process, and hopefully we can get in before the development of significant kidney disease,” said Dr. Zoungas, an endocrinologist with the Monash University School of Public Health and Preventive Medicine in Clayton, Australia.

“The lesser benefit in those with moderately reduced kidney function (CKD stage 3 or greater) may indicate that the glucose-independent mechanisms of renal progression may predominate in the later stages of the disease,” she speculated.

These new data are helpful for real-world clinical care, according to session co-moderator Dr. David A. D’Alessio, a professor of medicine and director of the division of endocrinology, metabolism, and nutrition at Duke University, Durham, N.C.

“I think this study was really important. It shows the strength of doing a good trial and then not stopping at 5 years, but continuing to collect data,” he said in an interview. “These studies end up being really useful to practitioners because we oftentimes see patients whom we’ve followed for up to 10 years.”

The patients studied had participated in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), which tested both intensive glucose control and blood pressure–lowering therapy. After the 5-year trial, patients returned to their usual practitioners’ care but had continued collection of data. The ADVANCE post-trial observational study (ADVANCE-ON) analyses were conducted after a median total follow-up of 9.9 years. Main findings were previously published (N Engl J Med. 2014;371:1392-406).

The greater reduction in hemoglobin A1c levels seen with intensive glucose control versus standard control on the trial was lost after the trial ended, Dr. Zoungas noted. “So if there was any effect in ADVANCE-ON, it would be attributable to the difference achieved during the in-trial period,” she said.

Compared with peers in the standard control group, patients in the intensive control group had a reduction in the risk of end-stage kidney disease during the entire follow-up (hazard ratio, 0.54) similar to that seen while they were on the trial (hazard ratio, 0.35).

In subgroup analyses, the lower the baseline stage of CKD, the greater the edge of intensive glucose control over standard glucose control for reducing the risk of end-stage kidney disease. The hazard ratio was 0.16 for patients with no CKD at baseline, 0.34 for those with stage 1 or 2, and 0.89 for patients with stage 3 or higher (P = .04). The number needed to treat for 5 years to prevent one case of end-stage kidney disease during the entire follow-up was 259, 109, and 393, respectively.

“What’s interesting to note here is that during the overall 9.9 years of follow-up, we have smaller numbers needed to treat for those with no evidence of CKD or early-stage CKD,” Dr. Zoungas said.

The investigators explored treatment impact on all-cause mortality and cardiovascular mortality according to baseline CKD stage, prompted by findings from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showing increased risks of these outcomes in patients with mild to moderate CKD at baseline who received intensive glucose control (Kidney Int. 2015;87:649-59).

ADVANCE-ON results, in contrast, showed no significant elevation in risk with intensive control, either while patients were on the trial or for the total 9.9 years of follow-up even in those at the more advanced stages of CKD, Dr. Zoungas said.

The relative risk of severe hypoglycemia was similarly elevated with intensive control, compared with standard control across CKD subgroups, although the absolute risk was higher for those with stage 3 or higher disease.

Dr. Zoungas disclosed that she receives honoraria from Servier for speaking about ADVANCE and ADVANCE-ON at scientific meetings, and that she is on the speakers bureau and advisory boards for and receives travel support from Merck Sharp & Dohme and AstraZeneca/Bristol-Myers Squibb. The study was funded in part by Servier.

VANCOUVER – Intensive glucose control needs to begin early in the course of kidney disease to have its greatest renal protective effect in patients with type 2 diabetes, suggests a study reported at the World Diabetes Congress.

The conclusions are based on long-term follow-up of patients with type 2 diabetes and high vascular risk who were treated on an international randomized trial for about 5 years with either intensive or standard glucose control.

Results for the 8,494 patients at a median total follow-up of nearly a decade showed that patients with lesser stages of chronic kidney disease (CKD) at the start of the study benefited more from intensive over standard glucose control in reducing the risk of onset of dialysis or renal transplantation, reported Dr. Sophia Zoungas.

Reassuringly, intensive glucose lowering was not associated with an increase in the risk of death or cardiovascular death, regardless of patients’ CKD stage at baseline. And the higher relative risk of severe hypoglycemia with the intensive strategy was likewise similar across baseline CKD stages.

“We think that the commencement of intensive glucose control is particularly important early in the disease process, and hopefully we can get in before the development of significant kidney disease,” said Dr. Zoungas, an endocrinologist with the Monash University School of Public Health and Preventive Medicine in Clayton, Australia.

“The lesser benefit in those with moderately reduced kidney function (CKD stage 3 or greater) may indicate that the glucose-independent mechanisms of renal progression may predominate in the later stages of the disease,” she speculated.

These new data are helpful for real-world clinical care, according to session co-moderator Dr. David A. D’Alessio, a professor of medicine and director of the division of endocrinology, metabolism, and nutrition at Duke University, Durham, N.C.

“I think this study was really important. It shows the strength of doing a good trial and then not stopping at 5 years, but continuing to collect data,” he said in an interview. “These studies end up being really useful to practitioners because we oftentimes see patients whom we’ve followed for up to 10 years.”

The patients studied had participated in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), which tested both intensive glucose control and blood pressure–lowering therapy. After the 5-year trial, patients returned to their usual practitioners’ care but had continued collection of data. The ADVANCE post-trial observational study (ADVANCE-ON) analyses were conducted after a median total follow-up of 9.9 years. Main findings were previously published (N Engl J Med. 2014;371:1392-406).

The greater reduction in hemoglobin A1c levels seen with intensive glucose control versus standard control on the trial was lost after the trial ended, Dr. Zoungas noted. “So if there was any effect in ADVANCE-ON, it would be attributable to the difference achieved during the in-trial period,” she said.

Compared with peers in the standard control group, patients in the intensive control group had a reduction in the risk of end-stage kidney disease during the entire follow-up (hazard ratio, 0.54) similar to that seen while they were on the trial (hazard ratio, 0.35).

In subgroup analyses, the lower the baseline stage of CKD, the greater the edge of intensive glucose control over standard glucose control for reducing the risk of end-stage kidney disease. The hazard ratio was 0.16 for patients with no CKD at baseline, 0.34 for those with stage 1 or 2, and 0.89 for patients with stage 3 or higher (P = .04). The number needed to treat for 5 years to prevent one case of end-stage kidney disease during the entire follow-up was 259, 109, and 393, respectively.

“What’s interesting to note here is that during the overall 9.9 years of follow-up, we have smaller numbers needed to treat for those with no evidence of CKD or early-stage CKD,” Dr. Zoungas said.

The investigators explored treatment impact on all-cause mortality and cardiovascular mortality according to baseline CKD stage, prompted by findings from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showing increased risks of these outcomes in patients with mild to moderate CKD at baseline who received intensive glucose control (Kidney Int. 2015;87:649-59).

ADVANCE-ON results, in contrast, showed no significant elevation in risk with intensive control, either while patients were on the trial or for the total 9.9 years of follow-up even in those at the more advanced stages of CKD, Dr. Zoungas said.

The relative risk of severe hypoglycemia was similarly elevated with intensive control, compared with standard control across CKD subgroups, although the absolute risk was higher for those with stage 3 or higher disease.

Dr. Zoungas disclosed that she receives honoraria from Servier for speaking about ADVANCE and ADVANCE-ON at scientific meetings, and that she is on the speakers bureau and advisory boards for and receives travel support from Merck Sharp & Dohme and AstraZeneca/Bristol-Myers Squibb. The study was funded in part by Servier.

VANCOUVER, B.C. – Alogliptin, an oral inhibitor of dipeptidyl peptidase 4 (DPP-4) having hypoglycemic activity, promoted regression of preclinical carotid atherosclerosis in patients with type 2 diabetes, judging from the findings of the randomized Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).

Among the 341 patients studied, all of whom were free of known cardiovascular disease at baseline, those in the alogliptin group had significant reductions in echocardiographic carotid intima-media thickness (IMT) at 2 years when compared with peers in a usual care group, according to data reported at the World Diabetes Congress.

“Our data may suggest … efficacy and benefit of alogliptin when used at an early stage of disease in preventing the progression of atherosclerosis,” commented first author Dr. Tomoya Mita, assistant professor in the department of metabolism and endocrinology at Juntendo University Graduate School of Medicine, Tokyo.

Three other trials – SAVOR TIMI 53, EXAMINE, and TECOS – have not found changes in cardiovascular outcomes with DPP-4 inhibitors among diabetic patients, he noted. Patients in those trials, however, had established cardiovascular disease or were at high risk.

“I’m not sure whether our data will translate into clinical outcome. But the magnitude of IMT reduction was identical to that of pioglitazone, [which] may reduce CV events,” Dr. Mita commented. “We are conducting a follow-up study that focuses on clinical outcome and safety, so we will find more detailed information in that study.”

“The importance of this study is really showing the limitations to cardiovascular outcome trials that have been going on,” commented Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, both in Washington, as well as chief scientific and medical officer of the American Diabetes Association in Alexandria, Va., who was session comoderator.

Those studies have been limited by selection bias, he agreed in an interview. “Taking patients who are so far advanced in their disease really isn’t the practical solution. We need to be thinking earlier, we need to be thinking in terms of prevention.”

Patients were recruited to SPEAD-A from diabetes outpatient clinics at 11 centers in Japan. They had to be 30 years of age or older and to have diabetes inadequately controlled by diet and lifestyle measures, or agents other than DPP-4 inhibitors, but with a glycated hemoglobin level of less than 9.4%.

Trial results, reported at the meeting and simultaneously published (Diabetes Care. 2016;39:18-27. doi: 10.2337/dc15-0781), showed that, relative to peers given usual care, patients given alogliptin (U.S. brand name Nesina) had greater reductions at 2 years in levels of glycated hemoglobin (−0.3% vs. −0.1%, P = .004) without a higher incidence of hypoglycemia.

Echocardiographic data revealed differences between the alogliptin group and the usual-care group in favor of the former with respect to changes in common carotid IMT (−0.026 mm vs. +0.005 mm, P = .022), right carotid maximum IMT (−0.045 mm vs. +0.011 mm, P = .025), and left carotid maximum IMT (−0.079 mm vs. −0.015 mm, P = .013).

Body mass index increased in the alogliptin group but decreased in the usual-care group (+0.3 kg/m2 vs. –0.3 kg/m², P = .003), Dr. Mita reported.

The groups were statistically indistinguishable with respect to insulin and fasting glucose levels, lipid profiles, blood pressure, markers of inflammation, and estimated glomerular filtration rate.

Rates of adverse events and serious adverse events were similar with alogliptin and usual care. There was no significant difference between groups in cardiovascular events, but only five patients experienced these events.

“I’m not sure how the DPP-4 inhibitor reduces the carotid intima-media thickness in this study,” Dr. Mita commented, but other research has suggested that drugs in this class decrease smooth muscle cell proliferation and inflammation and improve endothelial function.

Dr. Mita disclosed that he receives research funds from MSD and Takeda Pharma and that he receives lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical.

Financial support for the study was provided by Astellas Pharma, AstraZeneca, Bayer Holding, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Pfizer Japan, Sanofi, Sanwa Kagaku Kenkyusho, Shionogi, and Takeda

VANCOUVER, B.C. – Alogliptin, an oral inhibitor of dipeptidyl peptidase 4 (DPP-4) having hypoglycemic activity, promoted regression of preclinical carotid atherosclerosis in patients with type 2 diabetes, judging from the findings of the randomized Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).

Among the 341 patients studied, all of whom were free of known cardiovascular disease at baseline, those in the alogliptin group had significant reductions in echocardiographic carotid intima-media thickness (IMT) at 2 years when compared with peers in a usual care group, according to data reported at the World Diabetes Congress.

“Our data may suggest … efficacy and benefit of alogliptin when used at an early stage of disease in preventing the progression of atherosclerosis,” commented first author Dr. Tomoya Mita, assistant professor in the department of metabolism and endocrinology at Juntendo University Graduate School of Medicine, Tokyo.

Three other trials – SAVOR TIMI 53, EXAMINE, and TECOS – have not found changes in cardiovascular outcomes with DPP-4 inhibitors among diabetic patients, he noted. Patients in those trials, however, had established cardiovascular disease or were at high risk.

“I’m not sure whether our data will translate into clinical outcome. But the magnitude of IMT reduction was identical to that of pioglitazone, [which] may reduce CV events,” Dr. Mita commented. “We are conducting a follow-up study that focuses on clinical outcome and safety, so we will find more detailed information in that study.”

“The importance of this study is really showing the limitations to cardiovascular outcome trials that have been going on,” commented Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, both in Washington, as well as chief scientific and medical officer of the American Diabetes Association in Alexandria, Va., who was session comoderator.

Those studies have been limited by selection bias, he agreed in an interview. “Taking patients who are so far advanced in their disease really isn’t the practical solution. We need to be thinking earlier, we need to be thinking in terms of prevention.”

Patients were recruited to SPEAD-A from diabetes outpatient clinics at 11 centers in Japan. They had to be 30 years of age or older and to have diabetes inadequately controlled by diet and lifestyle measures, or agents other than DPP-4 inhibitors, but with a glycated hemoglobin level of less than 9.4%.

Trial results, reported at the meeting and simultaneously published (Diabetes Care. 2016;39:18-27. doi: 10.2337/dc15-0781), showed that, relative to peers given usual care, patients given alogliptin (U.S. brand name Nesina) had greater reductions at 2 years in levels of glycated hemoglobin (−0.3% vs. −0.1%, P = .004) without a higher incidence of hypoglycemia.

Echocardiographic data revealed differences between the alogliptin group and the usual-care group in favor of the former with respect to changes in common carotid IMT (−0.026 mm vs. +0.005 mm, P = .022), right carotid maximum IMT (−0.045 mm vs. +0.011 mm, P = .025), and left carotid maximum IMT (−0.079 mm vs. −0.015 mm, P = .013).

Body mass index increased in the alogliptin group but decreased in the usual-care group (+0.3 kg/m2 vs. –0.3 kg/m², P = .003), Dr. Mita reported.

The groups were statistically indistinguishable with respect to insulin and fasting glucose levels, lipid profiles, blood pressure, markers of inflammation, and estimated glomerular filtration rate.

Rates of adverse events and serious adverse events were similar with alogliptin and usual care. There was no significant difference between groups in cardiovascular events, but only five patients experienced these events.

“I’m not sure how the DPP-4 inhibitor reduces the carotid intima-media thickness in this study,” Dr. Mita commented, but other research has suggested that drugs in this class decrease smooth muscle cell proliferation and inflammation and improve endothelial function.

Dr. Mita disclosed that he receives research funds from MSD and Takeda Pharma and that he receives lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical.

Financial support for the study was provided by Astellas Pharma, AstraZeneca, Bayer Holding, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Pfizer Japan, Sanofi, Sanwa Kagaku Kenkyusho, Shionogi, and Takeda

VANCOUVER, B.C. – Alogliptin, an oral inhibitor of dipeptidyl peptidase 4 (DPP-4) having hypoglycemic activity, promoted regression of preclinical carotid atherosclerosis in patients with type 2 diabetes, judging from the findings of the randomized Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).

Among the 341 patients studied, all of whom were free of known cardiovascular disease at baseline, those in the alogliptin group had significant reductions in echocardiographic carotid intima-media thickness (IMT) at 2 years when compared with peers in a usual care group, according to data reported at the World Diabetes Congress.

“Our data may suggest … efficacy and benefit of alogliptin when used at an early stage of disease in preventing the progression of atherosclerosis,” commented first author Dr. Tomoya Mita, assistant professor in the department of metabolism and endocrinology at Juntendo University Graduate School of Medicine, Tokyo.

Three other trials – SAVOR TIMI 53, EXAMINE, and TECOS – have not found changes in cardiovascular outcomes with DPP-4 inhibitors among diabetic patients, he noted. Patients in those trials, however, had established cardiovascular disease or were at high risk.

“I’m not sure whether our data will translate into clinical outcome. But the magnitude of IMT reduction was identical to that of pioglitazone, [which] may reduce CV events,” Dr. Mita commented. “We are conducting a follow-up study that focuses on clinical outcome and safety, so we will find more detailed information in that study.”

“The importance of this study is really showing the limitations to cardiovascular outcome trials that have been going on,” commented Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, both in Washington, as well as chief scientific and medical officer of the American Diabetes Association in Alexandria, Va., who was session comoderator.

Those studies have been limited by selection bias, he agreed in an interview. “Taking patients who are so far advanced in their disease really isn’t the practical solution. We need to be thinking earlier, we need to be thinking in terms of prevention.”

Patients were recruited to SPEAD-A from diabetes outpatient clinics at 11 centers in Japan. They had to be 30 years of age or older and to have diabetes inadequately controlled by diet and lifestyle measures, or agents other than DPP-4 inhibitors, but with a glycated hemoglobin level of less than 9.4%.

Trial results, reported at the meeting and simultaneously published (Diabetes Care. 2016;39:18-27. doi: 10.2337/dc15-0781), showed that, relative to peers given usual care, patients given alogliptin (U.S. brand name Nesina) had greater reductions at 2 years in levels of glycated hemoglobin (−0.3% vs. −0.1%, P = .004) without a higher incidence of hypoglycemia.

Echocardiographic data revealed differences between the alogliptin group and the usual-care group in favor of the former with respect to changes in common carotid IMT (−0.026 mm vs. +0.005 mm, P = .022), right carotid maximum IMT (−0.045 mm vs. +0.011 mm, P = .025), and left carotid maximum IMT (−0.079 mm vs. −0.015 mm, P = .013).

Body mass index increased in the alogliptin group but decreased in the usual-care group (+0.3 kg/m2 vs. –0.3 kg/m², P = .003), Dr. Mita reported.

The groups were statistically indistinguishable with respect to insulin and fasting glucose levels, lipid profiles, blood pressure, markers of inflammation, and estimated glomerular filtration rate.

Rates of adverse events and serious adverse events were similar with alogliptin and usual care. There was no significant difference between groups in cardiovascular events, but only five patients experienced these events.

“I’m not sure how the DPP-4 inhibitor reduces the carotid intima-media thickness in this study,” Dr. Mita commented, but other research has suggested that drugs in this class decrease smooth muscle cell proliferation and inflammation and improve endothelial function.

Dr. Mita disclosed that he receives research funds from MSD and Takeda Pharma and that he receives lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical.

Financial support for the study was provided by Astellas Pharma, AstraZeneca, Bayer Holding, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Pfizer Japan, Sanofi, Sanwa Kagaku Kenkyusho, Shionogi, and Takeda

VANCOUVER – Patients with type 2 diabetes mellitus who lose weight after bariatric surgery experience a reduction in pancreatic triacylglycerol that is not seen in similarly treated nondiabetic individuals, according to a new study that sheds more light on the etiology and reversibility of this disease.

Dr. Roy Taylor and his colleagues performed specialized magnetic resonance imaging in 18 patients with diabetes and 9 matched control patients with normal glucose tolerance, all of whom underwent bariatric surgery.

Despite similar overall weight and fat loss in the diabetic and control groups at 8 weeks after surgery, pancreatic triacylglycerol had fallen by 18% in the former – corresponding to loss of about 0.6 g of fat from the organ – but remained essentially unchanged in the latter, he reported at the World Diabetes Congress.

The findings lend further support to the twin cycle hypothesis of type 2 diabetes, maintained Dr. Taylor, who is a professor with the Institute of Cellular Medicine, Department of Diabetes & Metabolism, Newcastle upon Tyne, England.

According to this hypothesis, positive caloric balance and pre-existing insulin resistance set up dual reinforcing vicious cycles, whereby fat accumulates first in the liver and then in the pancreas, including the islets (Diabetologia. 2008 Oct;51:1781-9). Chronic exposure of beta cells to fat ultimately leads to reduced acute secretion of insulin, contributing to elevated plasma glucose levels.

“Weight loss over 8 weeks brings about loss of pancreatic triglyceride specifically in type 2 diabetes,” he concluded of the study. “[I]t is likely that type 2 diabetes is caused by less than 1 g of fat in the pancreas.”

One session attendee wondered about the role of initially elevated insulin levels in the development of type 2 diabetes. “Do you have any data that reducing insulin levels, not through weight loss or hypocaloric diet, can do the same thing?” he asked.

“Yes, the pre-existing raised insulin levels will be a vital part of the genesis of type 2 diabetes,” Dr. Taylor replied. “Are there other ways to reducing that? Well, I have to say that I don’t know any better way of reducing plasma insulin than weight loss. It has a profound effect: the insulin levels come down entirely into the normal range. If there was some other clever way of doing it, we would expect that to help. But in the practical world, I think we are left with weight loss as the most likely way ahead.”

Another attendee wondered whether the change in pancreatic triacylglycerol was an epiphenomenon. “If you looked at some other tissue and measured triglycerides in the kidney or the heart, would you see a similar relationship? Or is there a way to show that this is actually producing a change in insulin secretion independent of the triglyceride change itself?” he asked.

“I think the clearest data come from the in vitro studies where we can manipulate the islets and show that it will produce the effect,” Dr. Taylor replied, additionally pointing to a recent study in mice in which knocking out fatty acid receptors specifically in the pancreas stopped the development of diabetes in response to obesity (Nat Med. 2015 Feb;21:173-7).

“So I think we have a clear biological model that will be difficult to show in humans. But I would suggest that in view of the totality of the evidence, it’s now beyond a reasonable doubt that we are looking at a causal effect,” he said.

Giving more background to his study, Dr. Taylor noted that previous research has shown that as pancreatic fat content declines in diabetic patients, insulin secretion normalizes (Diabetologia. 2011 Oct;54:2506-14).

“But critics pointed out that if people lose substantial weight, well, of course the fat in the organ will go down. It will happen in anyone, won’t it?” he said. “Well, if it happened only in people with diabetes, the causal relationship would be very strong. If on the other hand it happened in anyone, then perhaps it is a coincidence.”

The patients studied had diabetes for about 7 years, on average. They were matched for age, weight, and sex with control patients having normal glucose tolerance. All had Roux-en-Y gastric bypass surgery.

The investigators performed in-phase, out-of-phase magnetic resonance imaging before and 8 weeks after surgery to quantify the amount of triacylglycerol in the patients’ pancreas and liver.

Results reported at the meeting and simultaneously published (Diab Care. 2015 Dec 1. doi: 10.2337/dc15-0750) showed that after surgery, the control and diabetic groups had a similar reduction in weight (12.8% and 13.6%) and fat mass (11.3 and 13.6 kg).

The diabetic group had higher fasting plasma glucose levels, hepatic insulin resistance, and liver fat content at baseline, and experienced significant reductions into the normal range in all of these measures by 8 weeks, whereas values remained unchanged in the control group.

Pancreatic triacylglycerol content changed minimally in the control group (from 5.1% to 5.5%), but it fell significantly in the diabetic patients (from 6.6% to 5.4%, corresponding to loss of about 0.6 g of fat; P less than .005), according to Dr. Taylor, who disclosed that he had no relevant conflicts of interest.

In addition, the diabetic group had a significant increase in the first-phase insulin response to a stepped intravenous glucose infusion to normal levels (P less than .005), whereas the control group had no change.

VANCOUVER – Patients with type 2 diabetes mellitus who lose weight after bariatric surgery experience a reduction in pancreatic triacylglycerol that is not seen in similarly treated nondiabetic individuals, according to a new study that sheds more light on the etiology and reversibility of this disease.

Dr. Roy Taylor and his colleagues performed specialized magnetic resonance imaging in 18 patients with diabetes and 9 matched control patients with normal glucose tolerance, all of whom underwent bariatric surgery.

Despite similar overall weight and fat loss in the diabetic and control groups at 8 weeks after surgery, pancreatic triacylglycerol had fallen by 18% in the former – corresponding to loss of about 0.6 g of fat from the organ – but remained essentially unchanged in the latter, he reported at the World Diabetes Congress.

The findings lend further support to the twin cycle hypothesis of type 2 diabetes, maintained Dr. Taylor, who is a professor with the Institute of Cellular Medicine, Department of Diabetes & Metabolism, Newcastle upon Tyne, England.

According to this hypothesis, positive caloric balance and pre-existing insulin resistance set up dual reinforcing vicious cycles, whereby fat accumulates first in the liver and then in the pancreas, including the islets (Diabetologia. 2008 Oct;51:1781-9). Chronic exposure of beta cells to fat ultimately leads to reduced acute secretion of insulin, contributing to elevated plasma glucose levels.

“Weight loss over 8 weeks brings about loss of pancreatic triglyceride specifically in type 2 diabetes,” he concluded of the study. “[I]t is likely that type 2 diabetes is caused by less than 1 g of fat in the pancreas.”

One session attendee wondered about the role of initially elevated insulin levels in the development of type 2 diabetes. “Do you have any data that reducing insulin levels, not through weight loss or hypocaloric diet, can do the same thing?” he asked.

“Yes, the pre-existing raised insulin levels will be a vital part of the genesis of type 2 diabetes,” Dr. Taylor replied. “Are there other ways to reducing that? Well, I have to say that I don’t know any better way of reducing plasma insulin than weight loss. It has a profound effect: the insulin levels come down entirely into the normal range. If there was some other clever way of doing it, we would expect that to help. But in the practical world, I think we are left with weight loss as the most likely way ahead.”

Another attendee wondered whether the change in pancreatic triacylglycerol was an epiphenomenon. “If you looked at some other tissue and measured triglycerides in the kidney or the heart, would you see a similar relationship? Or is there a way to show that this is actually producing a change in insulin secretion independent of the triglyceride change itself?” he asked.

“I think the clearest data come from the in vitro studies where we can manipulate the islets and show that it will produce the effect,” Dr. Taylor replied, additionally pointing to a recent study in mice in which knocking out fatty acid receptors specifically in the pancreas stopped the development of diabetes in response to obesity (Nat Med. 2015 Feb;21:173-7).

“So I think we have a clear biological model that will be difficult to show in humans. But I would suggest that in view of the totality of the evidence, it’s now beyond a reasonable doubt that we are looking at a causal effect,” he said.

Giving more background to his study, Dr. Taylor noted that previous research has shown that as pancreatic fat content declines in diabetic patients, insulin secretion normalizes (Diabetologia. 2011 Oct;54:2506-14).

“But critics pointed out that if people lose substantial weight, well, of course the fat in the organ will go down. It will happen in anyone, won’t it?” he said. “Well, if it happened only in people with diabetes, the causal relationship would be very strong. If on the other hand it happened in anyone, then perhaps it is a coincidence.”

The patients studied had diabetes for about 7 years, on average. They were matched for age, weight, and sex with control patients having normal glucose tolerance. All had Roux-en-Y gastric bypass surgery.

The investigators performed in-phase, out-of-phase magnetic resonance imaging before and 8 weeks after surgery to quantify the amount of triacylglycerol in the patients’ pancreas and liver.

Results reported at the meeting and simultaneously published (Diab Care. 2015 Dec 1. doi: 10.2337/dc15-0750) showed that after surgery, the control and diabetic groups had a similar reduction in weight (12.8% and 13.6%) and fat mass (11.3 and 13.6 kg).

The diabetic group had higher fasting plasma glucose levels, hepatic insulin resistance, and liver fat content at baseline, and experienced significant reductions into the normal range in all of these measures by 8 weeks, whereas values remained unchanged in the control group.

Pancreatic triacylglycerol content changed minimally in the control group (from 5.1% to 5.5%), but it fell significantly in the diabetic patients (from 6.6% to 5.4%, corresponding to loss of about 0.6 g of fat; P less than .005), according to Dr. Taylor, who disclosed that he had no relevant conflicts of interest.

In addition, the diabetic group had a significant increase in the first-phase insulin response to a stepped intravenous glucose infusion to normal levels (P less than .005), whereas the control group had no change.

VANCOUVER – Patients with type 2 diabetes mellitus who lose weight after bariatric surgery experience a reduction in pancreatic triacylglycerol that is not seen in similarly treated nondiabetic individuals, according to a new study that sheds more light on the etiology and reversibility of this disease.

Dr. Roy Taylor and his colleagues performed specialized magnetic resonance imaging in 18 patients with diabetes and 9 matched control patients with normal glucose tolerance, all of whom underwent bariatric surgery.

Despite similar overall weight and fat loss in the diabetic and control groups at 8 weeks after surgery, pancreatic triacylglycerol had fallen by 18% in the former – corresponding to loss of about 0.6 g of fat from the organ – but remained essentially unchanged in the latter, he reported at the World Diabetes Congress.

The findings lend further support to the twin cycle hypothesis of type 2 diabetes, maintained Dr. Taylor, who is a professor with the Institute of Cellular Medicine, Department of Diabetes & Metabolism, Newcastle upon Tyne, England.

According to this hypothesis, positive caloric balance and pre-existing insulin resistance set up dual reinforcing vicious cycles, whereby fat accumulates first in the liver and then in the pancreas, including the islets (Diabetologia. 2008 Oct;51:1781-9). Chronic exposure of beta cells to fat ultimately leads to reduced acute secretion of insulin, contributing to elevated plasma glucose levels.

“Weight loss over 8 weeks brings about loss of pancreatic triglyceride specifically in type 2 diabetes,” he concluded of the study. “[I]t is likely that type 2 diabetes is caused by less than 1 g of fat in the pancreas.”

One session attendee wondered about the role of initially elevated insulin levels in the development of type 2 diabetes. “Do you have any data that reducing insulin levels, not through weight loss or hypocaloric diet, can do the same thing?” he asked.

“Yes, the pre-existing raised insulin levels will be a vital part of the genesis of type 2 diabetes,” Dr. Taylor replied. “Are there other ways to reducing that? Well, I have to say that I don’t know any better way of reducing plasma insulin than weight loss. It has a profound effect: the insulin levels come down entirely into the normal range. If there was some other clever way of doing it, we would expect that to help. But in the practical world, I think we are left with weight loss as the most likely way ahead.”

Another attendee wondered whether the change in pancreatic triacylglycerol was an epiphenomenon. “If you looked at some other tissue and measured triglycerides in the kidney or the heart, would you see a similar relationship? Or is there a way to show that this is actually producing a change in insulin secretion independent of the triglyceride change itself?” he asked.

“I think the clearest data come from the in vitro studies where we can manipulate the islets and show that it will produce the effect,” Dr. Taylor replied, additionally pointing to a recent study in mice in which knocking out fatty acid receptors specifically in the pancreas stopped the development of diabetes in response to obesity (Nat Med. 2015 Feb;21:173-7).

“So I think we have a clear biological model that will be difficult to show in humans. But I would suggest that in view of the totality of the evidence, it’s now beyond a reasonable doubt that we are looking at a causal effect,” he said.

Giving more background to his study, Dr. Taylor noted that previous research has shown that as pancreatic fat content declines in diabetic patients, insulin secretion normalizes (Diabetologia. 2011 Oct;54:2506-14).

“But critics pointed out that if people lose substantial weight, well, of course the fat in the organ will go down. It will happen in anyone, won’t it?” he said. “Well, if it happened only in people with diabetes, the causal relationship would be very strong. If on the other hand it happened in anyone, then perhaps it is a coincidence.”

The patients studied had diabetes for about 7 years, on average. They were matched for age, weight, and sex with control patients having normal glucose tolerance. All had Roux-en-Y gastric bypass surgery.

The investigators performed in-phase, out-of-phase magnetic resonance imaging before and 8 weeks after surgery to quantify the amount of triacylglycerol in the patients’ pancreas and liver.

Results reported at the meeting and simultaneously published (Diab Care. 2015 Dec 1. doi: 10.2337/dc15-0750) showed that after surgery, the control and diabetic groups had a similar reduction in weight (12.8% and 13.6%) and fat mass (11.3 and 13.6 kg).

The diabetic group had higher fasting plasma glucose levels, hepatic insulin resistance, and liver fat content at baseline, and experienced significant reductions into the normal range in all of these measures by 8 weeks, whereas values remained unchanged in the control group.

Pancreatic triacylglycerol content changed minimally in the control group (from 5.1% to 5.5%), but it fell significantly in the diabetic patients (from 6.6% to 5.4%, corresponding to loss of about 0.6 g of fat; P less than .005), according to Dr. Taylor, who disclosed that he had no relevant conflicts of interest.

In addition, the diabetic group had a significant increase in the first-phase insulin response to a stepped intravenous glucose infusion to normal levels (P less than .005), whereas the control group had no change.

SEATTLE – Research in colorectal cancer should focus on part on a handful of high-priority needs for prognostic and predictive biomarkers, according to Dr. William M. Grady, an oncologist at the Fred Hutchinson Cancer Research Center and section chief of gastroenterology at the University of Washington, Seattle.

“These needs are in the selection of optimal agents for the stage II and III cancers, the ones for which we add adjuvant therapy,” he told attendees of a joint meeting by the Global Biomarkers Consortium and the World Cutaneous Malignancies Congress. Additionally, “in the clinic, the main issue is selecting stage II patients who are at high risk for recurrence who may benefit from adjuvant therapy, and then stage III patients who will not benefit from therapy.”

There are some high-priority needs in the metastatic setting as well. “For stage IV disease, really the issue is selecting candidates for conventional chemotherapy, and here we are trying to balance toxicity versus survival and quality of life. Also, there is the issue of identifying people who will be optimal responders to some of the targeted therapies,” Dr. Grady elaborated.

The quest for biomarkers has been aided by increasing recognition of the molecular heterogeneity of colorectal cancer. Research has thus far identified three predominant molecular groups – a microsatellite unstable group, a microsatellite stable group, and a CIMP (CpG island methylator phenotype) group – having alterations of different signaling pathways. “This is clearly an oversimplification, and where I think we are going is that we will continue to parse out hopefully finer and finer groups that will be used for directing clinical care based on the response to agents that are being developed,” he said.

Microsatellite instability

Microsatellite instability is already used clinically to screen colorectal cancers in patients younger than 50 for hereditary Lynch syndrome, as recommended in national guidelines, according to Dr. Grady.

It can also be used to assess the prognosis of stage II and III disease, as patients with tumors showing microsatellite instability have better survival (J Clin Oncol. 2005;23[3]:609-18). But studies have been mixed on whether this biomarker is predictive for the response to adjuvant 5-fluorouracil–based chemotherapy (Nat Rev Clin Oncol. 2010;7[4]:197-208).

“Right now, the consensus is that for stage II disease, if there is microsatellite instability, that correlates with a very low-risk group and there doesn’t appear to be any benefit from adding adjuvant therapy; in fact, one study even suggested harm,” he noted. “For stage III disease [with microsatellite instability], there is no change … indicated at this time for 5-[fluorouracil]-based therapy; potentially, some people even argue that you might want to avoid this therapy, although I don’t think that’s the general opinion. And there may be a benefit in these tumors from the use of oxaliplatin, which one study last year suggested.”

In patients with stage IV disease, recent data suggest microsatellite instability may be a marker for benefit from therapies that target the programmed death–1 (PD1) pathway such as pembrolizumab (Keytruda) (N Engl J Med. 2015;372[26]:2509-20). “The challenge here is that only about 2% to 3% of metastatic colon cancers have microsatellite instability, so unfortunately it’s a small group that will benefit,” Dr. Grady commented.

Multigene signatures

A pair of clinically available multigene signatures, Oncotype DX–Colon and ColoPrint, are being used to estimate prognosis in patients with early disease. However, differences between adjacent assay-defined risk strata are fairly small, on the order of an absolute 10% or so. “This raises a question about what the clinical utility of these scores is,” he said.

“The real question we want to know, though, is can we use [these signatures] to choose people who will get adjuvant therapy for stage II disease,” he commented. At present, the answer appears to be a qualified yes for Oncotype DX, with some data suggesting that the survival benefit of chemotherapy may be greatest in patients with early disease who fall into the assay-defined high-risk category (J Clin Oncol. 2013;31[36]:4512-9)

“Where the ColoPrint assay seems to potentially have the highest benefit is in identifying a low- and high-risk group in the patients who have T3N0 disease but that’s microsatellite-stable. It doesn’t add much to those who have tumors that are already identified as being microsatellite-unstable or who have large [T4N0] disease that is microsatellite-stable,” he noted (Oncologist. 2015;20[2]:127-33).

Ultimately, use of Oncotype DX and ColoPrint should be individualized, according to Dr. Grady. “They certainly can be used, but they really need to be discussed on a case-by-case basis with the patient and physician because they have unclear clinical utility,” he said.

CIMP biomarker

Research suggests that CIMP provides prognostic information in patients with colorectal cancer, according to Dr. Grady. But it also may predict benefit from the addition of irinotecan to 5-fluorouracil and leucovorin in patients with stage III disease having intact mismatch repair (Gastroenterology. 2014;147[3]:637-45).

“CIMP is a potentially emerging marker for the use of cytotoxic agents, probably the most promising one today,” he commented.

Extended RAS assay

The extended RAS assay, which evaluates the whole exome for mutations in both KRAS and NRAS, is useful for guiding decisions about therapies that target signaling through the epidermal growth factor receptor (EGFR), such as panitumumab (Vectibix). However, its value is mainly limited to identifying patients who will not respond to this therapy, according to Dr. Grady.

By incorporating NRAS, this combination assay picks up an additional 10% of patients who will not respond to anti-EGFR therapy (J Clin Oncol. 2015;33[7]:682-5). But even so, it identifies only about a third of all nonresponders.

“We really need better biomarkers to identify patients who will respond, as well as identifying those patients who will not respond,” he said. “There is still a huge need for positive predictive biomarkers for the anti-VEGF [vascular endothelial growth factor] therapies and the anti-EGFR therapies, as well as for the cytotoxic therapies and the immune checkpoint inhibitors.”

Emerging biomarkers

The emerging colorectal cancer biomarkers include a variety of cancer genome mutation panels for assessing treatment options in patients with metastatic disease: OncoPlex, Foundation Medicine panels, and SNaPshot.

The clinical utility of these assays at present is still unclear. For example, the OncoPlex assay assesses tumors for 194 genes, only a subset of which are currently actionable or may be in the near future.

“Where you go with this is the real challenge,” Dr. Grady said. He referred clinicians to My Cancer Genome, a website managed by the Vanderbilt-Ingram Cancer Center that provides information about the specific mutations found with these panels.

The site additionally offers a concierge-like service called DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment) that may be helpful in individual cases. “That [service] will identify what the response for tumors that have specific mutations has been in previous clinical trials and any clinical trials that are ongoing for which your patient may be a candidate,” he explained.

Dr. Grady disclosed that he is a patent holder of methylated MLH1 and receives consulting fees from Myriad Genetics.

SEATTLE – Research in colorectal cancer should focus on part on a handful of high-priority needs for prognostic and predictive biomarkers, according to Dr. William M. Grady, an oncologist at the Fred Hutchinson Cancer Research Center and section chief of gastroenterology at the University of Washington, Seattle.

“These needs are in the selection of optimal agents for the stage II and III cancers, the ones for which we add adjuvant therapy,” he told attendees of a joint meeting by the Global Biomarkers Consortium and the World Cutaneous Malignancies Congress. Additionally, “in the clinic, the main issue is selecting stage II patients who are at high risk for recurrence who may benefit from adjuvant therapy, and then stage III patients who will not benefit from therapy.”

There are some high-priority needs in the metastatic setting as well. “For stage IV disease, really the issue is selecting candidates for conventional chemotherapy, and here we are trying to balance toxicity versus survival and quality of life. Also, there is the issue of identifying people who will be optimal responders to some of the targeted therapies,” Dr. Grady elaborated.

The quest for biomarkers has been aided by increasing recognition of the molecular heterogeneity of colorectal cancer. Research has thus far identified three predominant molecular groups – a microsatellite unstable group, a microsatellite stable group, and a CIMP (CpG island methylator phenotype) group – having alterations of different signaling pathways. “This is clearly an oversimplification, and where I think we are going is that we will continue to parse out hopefully finer and finer groups that will be used for directing clinical care based on the response to agents that are being developed,” he said.

Microsatellite instability

Microsatellite instability is already used clinically to screen colorectal cancers in patients younger than 50 for hereditary Lynch syndrome, as recommended in national guidelines, according to Dr. Grady.

It can also be used to assess the prognosis of stage II and III disease, as patients with tumors showing microsatellite instability have better survival (J Clin Oncol. 2005;23[3]:609-18). But studies have been mixed on whether this biomarker is predictive for the response to adjuvant 5-fluorouracil–based chemotherapy (Nat Rev Clin Oncol. 2010;7[4]:197-208).

“Right now, the consensus is that for stage II disease, if there is microsatellite instability, that correlates with a very low-risk group and there doesn’t appear to be any benefit from adding adjuvant therapy; in fact, one study even suggested harm,” he noted. “For stage III disease [with microsatellite instability], there is no change … indicated at this time for 5-[fluorouracil]-based therapy; potentially, some people even argue that you might want to avoid this therapy, although I don’t think that’s the general opinion. And there may be a benefit in these tumors from the use of oxaliplatin, which one study last year suggested.”

In patients with stage IV disease, recent data suggest microsatellite instability may be a marker for benefit from therapies that target the programmed death–1 (PD1) pathway such as pembrolizumab (Keytruda) (N Engl J Med. 2015;372[26]:2509-20). “The challenge here is that only about 2% to 3% of metastatic colon cancers have microsatellite instability, so unfortunately it’s a small group that will benefit,” Dr. Grady commented.

Multigene signatures

A pair of clinically available multigene signatures, Oncotype DX–Colon and ColoPrint, are being used to estimate prognosis in patients with early disease. However, differences between adjacent assay-defined risk strata are fairly small, on the order of an absolute 10% or so. “This raises a question about what the clinical utility of these scores is,” he said.

“The real question we want to know, though, is can we use [these signatures] to choose people who will get adjuvant therapy for stage II disease,” he commented. At present, the answer appears to be a qualified yes for Oncotype DX, with some data suggesting that the survival benefit of chemotherapy may be greatest in patients with early disease who fall into the assay-defined high-risk category (J Clin Oncol. 2013;31[36]:4512-9)

“Where the ColoPrint assay seems to potentially have the highest benefit is in identifying a low- and high-risk group in the patients who have T3N0 disease but that’s microsatellite-stable. It doesn’t add much to those who have tumors that are already identified as being microsatellite-unstable or who have large [T4N0] disease that is microsatellite-stable,” he noted (Oncologist. 2015;20[2]:127-33).

Ultimately, use of Oncotype DX and ColoPrint should be individualized, according to Dr. Grady. “They certainly can be used, but they really need to be discussed on a case-by-case basis with the patient and physician because they have unclear clinical utility,” he said.

CIMP biomarker

Research suggests that CIMP provides prognostic information in patients with colorectal cancer, according to Dr. Grady. But it also may predict benefit from the addition of irinotecan to 5-fluorouracil and leucovorin in patients with stage III disease having intact mismatch repair (Gastroenterology. 2014;147[3]:637-45).

“CIMP is a potentially emerging marker for the use of cytotoxic agents, probably the most promising one today,” he commented.

Extended RAS assay

The extended RAS assay, which evaluates the whole exome for mutations in both KRAS and NRAS, is useful for guiding decisions about therapies that target signaling through the epidermal growth factor receptor (EGFR), such as panitumumab (Vectibix). However, its value is mainly limited to identifying patients who will not respond to this therapy, according to Dr. Grady.

By incorporating NRAS, this combination assay picks up an additional 10% of patients who will not respond to anti-EGFR therapy (J Clin Oncol. 2015;33[7]:682-5). But even so, it identifies only about a third of all nonresponders.

“We really need better biomarkers to identify patients who will respond, as well as identifying those patients who will not respond,” he said. “There is still a huge need for positive predictive biomarkers for the anti-VEGF [vascular endothelial growth factor] therapies and the anti-EGFR therapies, as well as for the cytotoxic therapies and the immune checkpoint inhibitors.”

Emerging biomarkers

The emerging colorectal cancer biomarkers include a variety of cancer genome mutation panels for assessing treatment options in patients with metastatic disease: OncoPlex, Foundation Medicine panels, and SNaPshot.

The clinical utility of these assays at present is still unclear. For example, the OncoPlex assay assesses tumors for 194 genes, only a subset of which are currently actionable or may be in the near future.

“Where you go with this is the real challenge,” Dr. Grady said. He referred clinicians to My Cancer Genome, a website managed by the Vanderbilt-Ingram Cancer Center that provides information about the specific mutations found with these panels.

The site additionally offers a concierge-like service called DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment) that may be helpful in individual cases. “That [service] will identify what the response for tumors that have specific mutations has been in previous clinical trials and any clinical trials that are ongoing for which your patient may be a candidate,” he explained.

Dr. Grady disclosed that he is a patent holder of methylated MLH1 and receives consulting fees from Myriad Genetics.

SEATTLE – Research in colorectal cancer should focus on part on a handful of high-priority needs for prognostic and predictive biomarkers, according to Dr. William M. Grady, an oncologist at the Fred Hutchinson Cancer Research Center and section chief of gastroenterology at the University of Washington, Seattle.

“These needs are in the selection of optimal agents for the stage II and III cancers, the ones for which we add adjuvant therapy,” he told attendees of a joint meeting by the Global Biomarkers Consortium and the World Cutaneous Malignancies Congress. Additionally, “in the clinic, the main issue is selecting stage II patients who are at high risk for recurrence who may benefit from adjuvant therapy, and then stage III patients who will not benefit from therapy.”

There are some high-priority needs in the metastatic setting as well. “For stage IV disease, really the issue is selecting candidates for conventional chemotherapy, and here we are trying to balance toxicity versus survival and quality of life. Also, there is the issue of identifying people who will be optimal responders to some of the targeted therapies,” Dr. Grady elaborated.

The quest for biomarkers has been aided by increasing recognition of the molecular heterogeneity of colorectal cancer. Research has thus far identified three predominant molecular groups – a microsatellite unstable group, a microsatellite stable group, and a CIMP (CpG island methylator phenotype) group – having alterations of different signaling pathways. “This is clearly an oversimplification, and where I think we are going is that we will continue to parse out hopefully finer and finer groups that will be used for directing clinical care based on the response to agents that are being developed,” he said.

Microsatellite instability

Microsatellite instability is already used clinically to screen colorectal cancers in patients younger than 50 for hereditary Lynch syndrome, as recommended in national guidelines, according to Dr. Grady.

It can also be used to assess the prognosis of stage II and III disease, as patients with tumors showing microsatellite instability have better survival (J Clin Oncol. 2005;23[3]:609-18). But studies have been mixed on whether this biomarker is predictive for the response to adjuvant 5-fluorouracil–based chemotherapy (Nat Rev Clin Oncol. 2010;7[4]:197-208).

“Right now, the consensus is that for stage II disease, if there is microsatellite instability, that correlates with a very low-risk group and there doesn’t appear to be any benefit from adding adjuvant therapy; in fact, one study even suggested harm,” he noted. “For stage III disease [with microsatellite instability], there is no change … indicated at this time for 5-[fluorouracil]-based therapy; potentially, some people even argue that you might want to avoid this therapy, although I don’t think that’s the general opinion. And there may be a benefit in these tumors from the use of oxaliplatin, which one study last year suggested.”

In patients with stage IV disease, recent data suggest microsatellite instability may be a marker for benefit from therapies that target the programmed death–1 (PD1) pathway such as pembrolizumab (Keytruda) (N Engl J Med. 2015;372[26]:2509-20). “The challenge here is that only about 2% to 3% of metastatic colon cancers have microsatellite instability, so unfortunately it’s a small group that will benefit,” Dr. Grady commented.

Multigene signatures

A pair of clinically available multigene signatures, Oncotype DX–Colon and ColoPrint, are being used to estimate prognosis in patients with early disease. However, differences between adjacent assay-defined risk strata are fairly small, on the order of an absolute 10% or so. “This raises a question about what the clinical utility of these scores is,” he said.

“The real question we want to know, though, is can we use [these signatures] to choose people who will get adjuvant therapy for stage II disease,” he commented. At present, the answer appears to be a qualified yes for Oncotype DX, with some data suggesting that the survival benefit of chemotherapy may be greatest in patients with early disease who fall into the assay-defined high-risk category (J Clin Oncol. 2013;31[36]:4512-9)

“Where the ColoPrint assay seems to potentially have the highest benefit is in identifying a low- and high-risk group in the patients who have T3N0 disease but that’s microsatellite-stable. It doesn’t add much to those who have tumors that are already identified as being microsatellite-unstable or who have large [T4N0] disease that is microsatellite-stable,” he noted (Oncologist. 2015;20[2]:127-33).

Ultimately, use of Oncotype DX and ColoPrint should be individualized, according to Dr. Grady. “They certainly can be used, but they really need to be discussed on a case-by-case basis with the patient and physician because they have unclear clinical utility,” he said.

CIMP biomarker

Research suggests that CIMP provides prognostic information in patients with colorectal cancer, according to Dr. Grady. But it also may predict benefit from the addition of irinotecan to 5-fluorouracil and leucovorin in patients with stage III disease having intact mismatch repair (Gastroenterology. 2014;147[3]:637-45).

“CIMP is a potentially emerging marker for the use of cytotoxic agents, probably the most promising one today,” he commented.

Extended RAS assay

The extended RAS assay, which evaluates the whole exome for mutations in both KRAS and NRAS, is useful for guiding decisions about therapies that target signaling through the epidermal growth factor receptor (EGFR), such as panitumumab (Vectibix). However, its value is mainly limited to identifying patients who will not respond to this therapy, according to Dr. Grady.

By incorporating NRAS, this combination assay picks up an additional 10% of patients who will not respond to anti-EGFR therapy (J Clin Oncol. 2015;33[7]:682-5). But even so, it identifies only about a third of all nonresponders.

“We really need better biomarkers to identify patients who will respond, as well as identifying those patients who will not respond,” he said. “There is still a huge need for positive predictive biomarkers for the anti-VEGF [vascular endothelial growth factor] therapies and the anti-EGFR therapies, as well as for the cytotoxic therapies and the immune checkpoint inhibitors.”

Emerging biomarkers

The emerging colorectal cancer biomarkers include a variety of cancer genome mutation panels for assessing treatment options in patients with metastatic disease: OncoPlex, Foundation Medicine panels, and SNaPshot.

The clinical utility of these assays at present is still unclear. For example, the OncoPlex assay assesses tumors for 194 genes, only a subset of which are currently actionable or may be in the near future.

“Where you go with this is the real challenge,” Dr. Grady said. He referred clinicians to My Cancer Genome, a website managed by the Vanderbilt-Ingram Cancer Center that provides information about the specific mutations found with these panels.

The site additionally offers a concierge-like service called DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment) that may be helpful in individual cases. “That [service] will identify what the response for tumors that have specific mutations has been in previous clinical trials and any clinical trials that are ongoing for which your patient may be a candidate,” he explained.

Dr. Grady disclosed that he is a patent holder of methylated MLH1 and receives consulting fees from Myriad Genetics.

SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?

Diagnostic criteria

The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.

Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).

“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.

This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”

Staging criteria

The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.

The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).

“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”

Primary therapy

Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.

“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”

Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.

The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.

Risk-adapted management

Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”

There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).

“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.

Stem cell transplant

“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.

Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.

“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”

Maintenance therapy post transplant

The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.

“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.

Options for relapsed disease

Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.

Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”

A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).

The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.

Investigational agents

Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).

Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.

Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).

“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?

Diagnostic criteria

The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.

Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).

“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.

This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”

Staging criteria

The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.

The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).

“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”

Primary therapy

Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.

“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”

Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.

The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.

Risk-adapted management

Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”

There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).

“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.

Stem cell transplant

“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.

Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.

“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”

Maintenance therapy post transplant

The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.

“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.

Options for relapsed disease

Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.

Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”

A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).

The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.

Investigational agents

Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).

Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.

Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).

“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?

Diagnostic criteria

The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.

Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).

“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.

This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”

Staging criteria

The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.

The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).

“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”

Primary therapy

Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.

“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”

Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.

The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.

Risk-adapted management

Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”

There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).

“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.

Stem cell transplant

“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.

Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.

“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”

Maintenance therapy post transplant

The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.

“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.

Options for relapsed disease

Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.

Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”

A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).

The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.

Investigational agents

Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).

Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.

Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).

“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.