Beginning this year, the CPT® code for endobronchial ultrasound (EBUS) 31620 was replaced by three new codes that more accurately describe the procedure as it is currently performed. Codes 31652 and 31653 are reported when EBUS is used for sampling proximal lesions (mediastinal or hilar). Code 31654 is used in identifying more distal lesions. As with other bronchoscopy procedures, the diagnostic code, 31622, is included with these three new codes and the multiple endoscopy rule applies.

CPT code 31652 is utilized when one samples two or fewer proximal locations. CPT code 31653 is utilized when one samples three or more proximal locations. 31652 and 31653 may not be used together; use the code that best describes the work that was done. These two codes include the sampling procedures and, therefore, one does not use CPT codes for sampling, e.g., 31628 or 31629, with either 31652 or 31653. However, if additional procedures are performed on structures distal to the hila, then it is appropriate to use other bronchoscopy codes with 31652 and 31653.

CPT code 31654 is an “add-on” code that is used to identify more peripheral lesions for sampling. As such, it may be used with all of the other bronchoscopy codes.

Unfortunately, when CMS originally published the National Correct Coding Initiative (NCCI) edits for these new codes, there were errors present. NCCI edits are used to instruct CMS payers and clinicians when two distinct CPT codes may or may not be used together. The NCCI edits for 31652 and 31653 published on January 1, 2016, had a value of “0” for all other bronchoscopy codes; this instructed payers to reject any claims for 31652 or 31653 if any other bronchoscopy code was appended. The societies alerted CMS to these problems, and the NCCI edits were corrected. However, these corrections did not take effect until April 1, 2016. It is, therefore, quite possible that some claims will have been rejected by CMS and other carriers from January 1 until March 31. All claims for EBUS procedures during this time should be reviewed and resubmitted if rejected. You have 1 year to resubmit these claims to avoid nonpayment for untimely filing.

Beginning this year, the CPT® code for endobronchial ultrasound (EBUS) 31620 was replaced by three new codes that more accurately describe the procedure as it is currently performed. Codes 31652 and 31653 are reported when EBUS is used for sampling proximal lesions (mediastinal or hilar). Code 31654 is used in identifying more distal lesions. As with other bronchoscopy procedures, the diagnostic code, 31622, is included with these three new codes and the multiple endoscopy rule applies.

CPT code 31652 is utilized when one samples two or fewer proximal locations. CPT code 31653 is utilized when one samples three or more proximal locations. 31652 and 31653 may not be used together; use the code that best describes the work that was done. These two codes include the sampling procedures and, therefore, one does not use CPT codes for sampling, e.g., 31628 or 31629, with either 31652 or 31653. However, if additional procedures are performed on structures distal to the hila, then it is appropriate to use other bronchoscopy codes with 31652 and 31653.

CPT code 31654 is an “add-on” code that is used to identify more peripheral lesions for sampling. As such, it may be used with all of the other bronchoscopy codes.

Unfortunately, when CMS originally published the National Correct Coding Initiative (NCCI) edits for these new codes, there were errors present. NCCI edits are used to instruct CMS payers and clinicians when two distinct CPT codes may or may not be used together. The NCCI edits for 31652 and 31653 published on January 1, 2016, had a value of “0” for all other bronchoscopy codes; this instructed payers to reject any claims for 31652 or 31653 if any other bronchoscopy code was appended. The societies alerted CMS to these problems, and the NCCI edits were corrected. However, these corrections did not take effect until April 1, 2016. It is, therefore, quite possible that some claims will have been rejected by CMS and other carriers from January 1 until March 31. All claims for EBUS procedures during this time should be reviewed and resubmitted if rejected. You have 1 year to resubmit these claims to avoid nonpayment for untimely filing.

Beginning this year, the CPT® code for endobronchial ultrasound (EBUS) 31620 was replaced by three new codes that more accurately describe the procedure as it is currently performed. Codes 31652 and 31653 are reported when EBUS is used for sampling proximal lesions (mediastinal or hilar). Code 31654 is used in identifying more distal lesions. As with other bronchoscopy procedures, the diagnostic code, 31622, is included with these three new codes and the multiple endoscopy rule applies.

CPT code 31652 is utilized when one samples two or fewer proximal locations. CPT code 31653 is utilized when one samples three or more proximal locations. 31652 and 31653 may not be used together; use the code that best describes the work that was done. These two codes include the sampling procedures and, therefore, one does not use CPT codes for sampling, e.g., 31628 or 31629, with either 31652 or 31653. However, if additional procedures are performed on structures distal to the hila, then it is appropriate to use other bronchoscopy codes with 31652 and 31653.

CPT code 31654 is an “add-on” code that is used to identify more peripheral lesions for sampling. As such, it may be used with all of the other bronchoscopy codes.

Unfortunately, when CMS originally published the National Correct Coding Initiative (NCCI) edits for these new codes, there were errors present. NCCI edits are used to instruct CMS payers and clinicians when two distinct CPT codes may or may not be used together. The NCCI edits for 31652 and 31653 published on January 1, 2016, had a value of “0” for all other bronchoscopy codes; this instructed payers to reject any claims for 31652 or 31653 if any other bronchoscopy code was appended. The societies alerted CMS to these problems, and the NCCI edits were corrected. However, these corrections did not take effect until April 1, 2016. It is, therefore, quite possible that some claims will have been rejected by CMS and other carriers from January 1 until March 31. All claims for EBUS procedures during this time should be reviewed and resubmitted if rejected. You have 1 year to resubmit these claims to avoid nonpayment for untimely filing.

LONDON, ENGLAND – Prompt referral to a rheumatologist and early initiation of treatment remain 2 of the 12 key recommendations in the updated European League Against Rheumatism guidelines for early arthritis.

There are now three specific recommendations dealing with referral and diagnosis; four that cover initial drug treatment with disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids; two that cover management strategy and monitoring; and three that cover nonpharmacologic interventions, prevention, and patient information and education.

While many of the recommendations have not radically changed, there have been revisions to the wording. In line with other EULAR recommendations for the management of rheumatic disease, the updated early arthritis guidelines also now contain three overarching principles. The first states that the management of early arthritis should aim to achieve the best possible care and emphasizes the need for shared decision making between rheumatologist and patient. The second states that a rheumatologist should be the main specialist looking after a patient with early arthritis, and the third states that a definitive diagnosis should be made only after a careful medical history and clinical examination have been undertaken.

“[The EULAR] recommendations deal especially with early-stage inflammatory arthritis,” said Dr. Bernard Combe of Hôpital Lapeyronie in Montpellier, France, who was the convener of the task force behind the updated guidelines. As such, they are universal for all rheumatologic arthritis conditions when diagnosed early, before they differentiate into more specifics, he said in an interview. That includes progression from early inflammatory arthritis to rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis.

Dr. Combe, who is also professor of rheumatology at Montpellier University and head of the bone and joint diseases department at Montpellier University Hospital, presented the updated EULAR guidance at the European Congress of Rheumatology. He noted that the guidelines were first written almost 10 years ago (Ann Rheum Dis. 2007 Jan;66(1):34-45) and so were in need of an update. A task force of 20 rheumatologists, two patients, and one health care professional representing 12 European countries were involved in the update that adhered to EULAR standard operating procedure of developing guidelines.

Although EULAR had published guidance on the management of arthritis in the intervening years, he said, this had focused more on management, and the aim of the early arthritis guidelines was to cover the “entire spectrum of the management of early inflammatory arthritis.”

The updated recommendations start and end with patient-centered statements, he observed. The first notes that patients with any joint swelling associated with pain or stiffness should be referred to and seen by a rheumatologist within 6 weeks of the onset of symptoms. The final recommendation deals with patient information and education about the disease, and programs aiming to help patients cope with pain, disability, and ensure their continued ability to work and participate in their usual social activities.

The concept of early identification and treatment is not new, Dr. Combe observed, but there is so much more evidence in support of initiating DMARD therapy within the first 3 months of referral, even if patients do not fulfill classification criteria for a specific inflammatory rheumatic disease.

In terms of diagnosis, the recommendations now hinge on performing a thorough clinical examination and using ultrasonography to confirm the presence of arthritis if needed. Magnetic resonance imaging (MRI) is no longer recommended in this initial diagnostic work up. This is due to the cost and often lack of widespread access in all European countries, Dr. Combe said. MRI might be considered later, however, if a diagnosis cannot be reached. Assessment of the number of swollen joints, acute phase reactants, and antibody tests (rheumatoid factor and anti-citrullinated protein antibody) also might be of use at this point.

Among the various DMARDs, methotrexate is recommended as the “anchor drug”; it should be used as part of the first treatment strategy in patients who are at risk of persistent disease, unless it contraindicated. The goal of treatment with DMARDs is to achieve clinical remission. Regular monitoring of disease activity, side effects, and comorbidities should be performed alongside their use. Regular monitoring of all pharmacologic therapy should include assessment of tender and swollen joint counts, global health assessments by the patient and the physician, and acute phase reactants.

As for NSAIDs, they are recommended for symptomatic relief, but “at the minimum effective dose for the shortest time possible.” The risks for gastrointestinal, renal, and cardiovascular complications should be carefully weighed against the likely benefits. Glucocorticoids also are recommended for reducing pain and swelling, and structural progression, but again these need to be used at the lowest possible dose and for no more than 6 months to avoid potential long-term side effects.

A recommendation on nonpharmacologic interventions also is included, which states that physical exercise and occupational therapy should be considered as adjunctive therapy.

In addition, the task force came up with a list of 10 research questions that need to be answered, which included items on risk prediction, optimal treatment combinations, and dosing regimens.

As with other EULAR guidelines, a flow chart is included that summarizes the recommendations to help guide physicians on when and how to treat, when to adapt dosing or change medication, and other treatments and approaches to consider.

There is a new recommendation on prevention highlighting the importance of smoking cessation, dental care, weight control, vaccination, and managing comorbidities.

Once the guidelines have been finalized, they will be published in the EULAR journal, Annals of the Rheumatic Diseases, later in the year.

Dr. Combe has received research grants and honoraria from Pfizer, Roche-Chugai, and UCB, and honoraria from Bristol-Myers Squibb, Janssen, Eli Lilly, Merck Sharpe and Dohme, and Novartis.

LONDON, ENGLAND – Prompt referral to a rheumatologist and early initiation of treatment remain 2 of the 12 key recommendations in the updated European League Against Rheumatism guidelines for early arthritis.

There are now three specific recommendations dealing with referral and diagnosis; four that cover initial drug treatment with disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids; two that cover management strategy and monitoring; and three that cover nonpharmacologic interventions, prevention, and patient information and education.

While many of the recommendations have not radically changed, there have been revisions to the wording. In line with other EULAR recommendations for the management of rheumatic disease, the updated early arthritis guidelines also now contain three overarching principles. The first states that the management of early arthritis should aim to achieve the best possible care and emphasizes the need for shared decision making between rheumatologist and patient. The second states that a rheumatologist should be the main specialist looking after a patient with early arthritis, and the third states that a definitive diagnosis should be made only after a careful medical history and clinical examination have been undertaken.

“[The EULAR] recommendations deal especially with early-stage inflammatory arthritis,” said Dr. Bernard Combe of Hôpital Lapeyronie in Montpellier, France, who was the convener of the task force behind the updated guidelines. As such, they are universal for all rheumatologic arthritis conditions when diagnosed early, before they differentiate into more specifics, he said in an interview. That includes progression from early inflammatory arthritis to rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis.

Dr. Combe, who is also professor of rheumatology at Montpellier University and head of the bone and joint diseases department at Montpellier University Hospital, presented the updated EULAR guidance at the European Congress of Rheumatology. He noted that the guidelines were first written almost 10 years ago (Ann Rheum Dis. 2007 Jan;66(1):34-45) and so were in need of an update. A task force of 20 rheumatologists, two patients, and one health care professional representing 12 European countries were involved in the update that adhered to EULAR standard operating procedure of developing guidelines.

Although EULAR had published guidance on the management of arthritis in the intervening years, he said, this had focused more on management, and the aim of the early arthritis guidelines was to cover the “entire spectrum of the management of early inflammatory arthritis.”

The updated recommendations start and end with patient-centered statements, he observed. The first notes that patients with any joint swelling associated with pain or stiffness should be referred to and seen by a rheumatologist within 6 weeks of the onset of symptoms. The final recommendation deals with patient information and education about the disease, and programs aiming to help patients cope with pain, disability, and ensure their continued ability to work and participate in their usual social activities.

The concept of early identification and treatment is not new, Dr. Combe observed, but there is so much more evidence in support of initiating DMARD therapy within the first 3 months of referral, even if patients do not fulfill classification criteria for a specific inflammatory rheumatic disease.

In terms of diagnosis, the recommendations now hinge on performing a thorough clinical examination and using ultrasonography to confirm the presence of arthritis if needed. Magnetic resonance imaging (MRI) is no longer recommended in this initial diagnostic work up. This is due to the cost and often lack of widespread access in all European countries, Dr. Combe said. MRI might be considered later, however, if a diagnosis cannot be reached. Assessment of the number of swollen joints, acute phase reactants, and antibody tests (rheumatoid factor and anti-citrullinated protein antibody) also might be of use at this point.

Among the various DMARDs, methotrexate is recommended as the “anchor drug”; it should be used as part of the first treatment strategy in patients who are at risk of persistent disease, unless it contraindicated. The goal of treatment with DMARDs is to achieve clinical remission. Regular monitoring of disease activity, side effects, and comorbidities should be performed alongside their use. Regular monitoring of all pharmacologic therapy should include assessment of tender and swollen joint counts, global health assessments by the patient and the physician, and acute phase reactants.

As for NSAIDs, they are recommended for symptomatic relief, but “at the minimum effective dose for the shortest time possible.” The risks for gastrointestinal, renal, and cardiovascular complications should be carefully weighed against the likely benefits. Glucocorticoids also are recommended for reducing pain and swelling, and structural progression, but again these need to be used at the lowest possible dose and for no more than 6 months to avoid potential long-term side effects.

A recommendation on nonpharmacologic interventions also is included, which states that physical exercise and occupational therapy should be considered as adjunctive therapy.

In addition, the task force came up with a list of 10 research questions that need to be answered, which included items on risk prediction, optimal treatment combinations, and dosing regimens.

As with other EULAR guidelines, a flow chart is included that summarizes the recommendations to help guide physicians on when and how to treat, when to adapt dosing or change medication, and other treatments and approaches to consider.

There is a new recommendation on prevention highlighting the importance of smoking cessation, dental care, weight control, vaccination, and managing comorbidities.

Once the guidelines have been finalized, they will be published in the EULAR journal, Annals of the Rheumatic Diseases, later in the year.

Dr. Combe has received research grants and honoraria from Pfizer, Roche-Chugai, and UCB, and honoraria from Bristol-Myers Squibb, Janssen, Eli Lilly, Merck Sharpe and Dohme, and Novartis.

LONDON, ENGLAND – Prompt referral to a rheumatologist and early initiation of treatment remain 2 of the 12 key recommendations in the updated European League Against Rheumatism guidelines for early arthritis.

There are now three specific recommendations dealing with referral and diagnosis; four that cover initial drug treatment with disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids; two that cover management strategy and monitoring; and three that cover nonpharmacologic interventions, prevention, and patient information and education.

While many of the recommendations have not radically changed, there have been revisions to the wording. In line with other EULAR recommendations for the management of rheumatic disease, the updated early arthritis guidelines also now contain three overarching principles. The first states that the management of early arthritis should aim to achieve the best possible care and emphasizes the need for shared decision making between rheumatologist and patient. The second states that a rheumatologist should be the main specialist looking after a patient with early arthritis, and the third states that a definitive diagnosis should be made only after a careful medical history and clinical examination have been undertaken.

“[The EULAR] recommendations deal especially with early-stage inflammatory arthritis,” said Dr. Bernard Combe of Hôpital Lapeyronie in Montpellier, France, who was the convener of the task force behind the updated guidelines. As such, they are universal for all rheumatologic arthritis conditions when diagnosed early, before they differentiate into more specifics, he said in an interview. That includes progression from early inflammatory arthritis to rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis.

Dr. Combe, who is also professor of rheumatology at Montpellier University and head of the bone and joint diseases department at Montpellier University Hospital, presented the updated EULAR guidance at the European Congress of Rheumatology. He noted that the guidelines were first written almost 10 years ago (Ann Rheum Dis. 2007 Jan;66(1):34-45) and so were in need of an update. A task force of 20 rheumatologists, two patients, and one health care professional representing 12 European countries were involved in the update that adhered to EULAR standard operating procedure of developing guidelines.

Although EULAR had published guidance on the management of arthritis in the intervening years, he said, this had focused more on management, and the aim of the early arthritis guidelines was to cover the “entire spectrum of the management of early inflammatory arthritis.”

The updated recommendations start and end with patient-centered statements, he observed. The first notes that patients with any joint swelling associated with pain or stiffness should be referred to and seen by a rheumatologist within 6 weeks of the onset of symptoms. The final recommendation deals with patient information and education about the disease, and programs aiming to help patients cope with pain, disability, and ensure their continued ability to work and participate in their usual social activities.

The concept of early identification and treatment is not new, Dr. Combe observed, but there is so much more evidence in support of initiating DMARD therapy within the first 3 months of referral, even if patients do not fulfill classification criteria for a specific inflammatory rheumatic disease.

In terms of diagnosis, the recommendations now hinge on performing a thorough clinical examination and using ultrasonography to confirm the presence of arthritis if needed. Magnetic resonance imaging (MRI) is no longer recommended in this initial diagnostic work up. This is due to the cost and often lack of widespread access in all European countries, Dr. Combe said. MRI might be considered later, however, if a diagnosis cannot be reached. Assessment of the number of swollen joints, acute phase reactants, and antibody tests (rheumatoid factor and anti-citrullinated protein antibody) also might be of use at this point.

Among the various DMARDs, methotrexate is recommended as the “anchor drug”; it should be used as part of the first treatment strategy in patients who are at risk of persistent disease, unless it contraindicated. The goal of treatment with DMARDs is to achieve clinical remission. Regular monitoring of disease activity, side effects, and comorbidities should be performed alongside their use. Regular monitoring of all pharmacologic therapy should include assessment of tender and swollen joint counts, global health assessments by the patient and the physician, and acute phase reactants.

As for NSAIDs, they are recommended for symptomatic relief, but “at the minimum effective dose for the shortest time possible.” The risks for gastrointestinal, renal, and cardiovascular complications should be carefully weighed against the likely benefits. Glucocorticoids also are recommended for reducing pain and swelling, and structural progression, but again these need to be used at the lowest possible dose and for no more than 6 months to avoid potential long-term side effects.

A recommendation on nonpharmacologic interventions also is included, which states that physical exercise and occupational therapy should be considered as adjunctive therapy.

In addition, the task force came up with a list of 10 research questions that need to be answered, which included items on risk prediction, optimal treatment combinations, and dosing regimens.

As with other EULAR guidelines, a flow chart is included that summarizes the recommendations to help guide physicians on when and how to treat, when to adapt dosing or change medication, and other treatments and approaches to consider.

There is a new recommendation on prevention highlighting the importance of smoking cessation, dental care, weight control, vaccination, and managing comorbidities.

Once the guidelines have been finalized, they will be published in the EULAR journal, Annals of the Rheumatic Diseases, later in the year.

Dr. Combe has received research grants and honoraria from Pfizer, Roche-Chugai, and UCB, and honoraria from Bristol-Myers Squibb, Janssen, Eli Lilly, Merck Sharpe and Dohme, and Novartis.

NEW ORLEANS – The second trial involving a sub-dermal matchstick-size osmotic mini-pump that releases exenatide over 6 months in people who have poorly controlled type 2 diabetes achieved superior blood glucose levels and weight loss after a year, compared with sitagliptin alone, Dr. Julio Rosenstock reported at the annual scientific sessions of the American Diabetes Association.

Dr. Rosenstock, director of the Dallas Diabetes and Endocrine Center, reported on the findings of the study, known as FREEDOM-2. The study randomized 535 adults with poorly controlled type 2 diabetes to either the mini-pump, known as the ITCA 650, that releases 60 μg of exenatide a day, or 100 mg of daily sitagliptin. This is a follow-on trial to FREEDOM-1 that compared the ICTA 650 mini-pump to twice-daily exenatide in people with type 2 diabetes who were taking metformin (Diabetes Care. 2013 Sep;36[9]:2559-65). All participants in FREEDOM-2 had been on metformin greater than or equal to 1,500 mg daily and had HbA1c greater than or equal to 7.5%.

©Boarding1Now/Thinkstock

“The continuous subcutaneous delivery of exenatide with ICTA 650 is a novel approach to improve glycemic control, ensuring adherence and consistent delivery of therapy for 6-12 months for people with type 2 diabetes,” Dr. Rosenstock said. The ICTA recipients first received a dose of 20 μg of exenatide daily for the first 12 weeks, then had that increased to 60 μg for the remainder of the study.

After 1 year, average reduction in HbA1c was 1.5% with ITCA 650 vs. 0.8% with sitagliptin, Dr. Rosenstock said. Sixty-one percent of those in the ITCA 650 group achieved greater than 0.5% reductions in HbA1c and more than 2 kg loss in body weight after a year, compared with 28% of the sitagliptin group.

Overall, the patients who receive the ITCA 650 achieved an average body weight reduction of 4 kg vs. 1.3 kg for the sitagliptin patients. Again, 61% of the ITCA patients achieved target HbA1c of less than 7% vs. 42% of the sitagliptin group. Rescue therapy was required in 15% with ITCA 650 and 35% with sitagliptin, and minor hypoglycemia occurred in 4.2% with ITCA 650 vs. 1.9% with sitagliptin.

The ICTA 650 group did have a higher incidence of adverse events, Dr. Rosenstock said, 82% vs. 74%. These included side effects at the application site like hematoma, bleeding, infection, or pain, as well as gastrointestinal (GI) problems such as nausea and vomiting. “The GI adverse events were similar to what we have seen with other GLP-1 receptor agonists,” Dr. Rosenstock said. “The incidence of nausea spiked at the initial insertion and then when we increased the dose from 20 μg to 60 μg, but the second time the ICTA 650 was replaced for 60 μg dosing, the nausea rates did not spike.” The ICTA 650 group had a discontinuation rate of 1%.

Each mini-pump inserted in the FREEDOM-2 trial had a duration of 6 months, but Dr. Rosenstock said the goal is to achieve extended-release dosing with a single mini-pump for 2 years.

Dr. Rosenstock disclosed he serves on the advisory panels of Boehringer Ingelheim Pharmaceuticals, Daiichi-Sankyo Co., Eli Lilly and Company, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, MannKind Corporation, Merck & Co., Novartis, Novo Nordisk, Sanofi U.S., and Takeda Pharmaceutical Company; and that he has received research support from Amylin Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, MannKind Corporation, Merck & Co., Novartis, Novo Nordisk, Pfizer, Roche Pharmaceuticals, Sanofi U.S. and Takeda.

NEW ORLEANS – The second trial involving a sub-dermal matchstick-size osmotic mini-pump that releases exenatide over 6 months in people who have poorly controlled type 2 diabetes achieved superior blood glucose levels and weight loss after a year, compared with sitagliptin alone, Dr. Julio Rosenstock reported at the annual scientific sessions of the American Diabetes Association.

Dr. Rosenstock, director of the Dallas Diabetes and Endocrine Center, reported on the findings of the study, known as FREEDOM-2. The study randomized 535 adults with poorly controlled type 2 diabetes to either the mini-pump, known as the ITCA 650, that releases 60 μg of exenatide a day, or 100 mg of daily sitagliptin. This is a follow-on trial to FREEDOM-1 that compared the ICTA 650 mini-pump to twice-daily exenatide in people with type 2 diabetes who were taking metformin (Diabetes Care. 2013 Sep;36[9]:2559-65). All participants in FREEDOM-2 had been on metformin greater than or equal to 1,500 mg daily and had HbA1c greater than or equal to 7.5%.

©Boarding1Now/Thinkstock

“The continuous subcutaneous delivery of exenatide with ICTA 650 is a novel approach to improve glycemic control, ensuring adherence and consistent delivery of therapy for 6-12 months for people with type 2 diabetes,” Dr. Rosenstock said. The ICTA recipients first received a dose of 20 μg of exenatide daily for the first 12 weeks, then had that increased to 60 μg for the remainder of the study.

After 1 year, average reduction in HbA1c was 1.5% with ITCA 650 vs. 0.8% with sitagliptin, Dr. Rosenstock said. Sixty-one percent of those in the ITCA 650 group achieved greater than 0.5% reductions in HbA1c and more than 2 kg loss in body weight after a year, compared with 28% of the sitagliptin group.

Overall, the patients who receive the ITCA 650 achieved an average body weight reduction of 4 kg vs. 1.3 kg for the sitagliptin patients. Again, 61% of the ITCA patients achieved target HbA1c of less than 7% vs. 42% of the sitagliptin group. Rescue therapy was required in 15% with ITCA 650 and 35% with sitagliptin, and minor hypoglycemia occurred in 4.2% with ITCA 650 vs. 1.9% with sitagliptin.

The ICTA 650 group did have a higher incidence of adverse events, Dr. Rosenstock said, 82% vs. 74%. These included side effects at the application site like hematoma, bleeding, infection, or pain, as well as gastrointestinal (GI) problems such as nausea and vomiting. “The GI adverse events were similar to what we have seen with other GLP-1 receptor agonists,” Dr. Rosenstock said. “The incidence of nausea spiked at the initial insertion and then when we increased the dose from 20 μg to 60 μg, but the second time the ICTA 650 was replaced for 60 μg dosing, the nausea rates did not spike.” The ICTA 650 group had a discontinuation rate of 1%.

Each mini-pump inserted in the FREEDOM-2 trial had a duration of 6 months, but Dr. Rosenstock said the goal is to achieve extended-release dosing with a single mini-pump for 2 years.

Dr. Rosenstock disclosed he serves on the advisory panels of Boehringer Ingelheim Pharmaceuticals, Daiichi-Sankyo Co., Eli Lilly and Company, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, MannKind Corporation, Merck & Co., Novartis, Novo Nordisk, Sanofi U.S., and Takeda Pharmaceutical Company; and that he has received research support from Amylin Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, MannKind Corporation, Merck & Co., Novartis, Novo Nordisk, Pfizer, Roche Pharmaceuticals, Sanofi U.S. and Takeda.

NEW ORLEANS – The second trial involving a sub-dermal matchstick-size osmotic mini-pump that releases exenatide over 6 months in people who have poorly controlled type 2 diabetes achieved superior blood glucose levels and weight loss after a year, compared with sitagliptin alone, Dr. Julio Rosenstock reported at the annual scientific sessions of the American Diabetes Association.

Dr. Rosenstock, director of the Dallas Diabetes and Endocrine Center, reported on the findings of the study, known as FREEDOM-2. The study randomized 535 adults with poorly controlled type 2 diabetes to either the mini-pump, known as the ITCA 650, that releases 60 μg of exenatide a day, or 100 mg of daily sitagliptin. This is a follow-on trial to FREEDOM-1 that compared the ICTA 650 mini-pump to twice-daily exenatide in people with type 2 diabetes who were taking metformin (Diabetes Care. 2013 Sep;36[9]:2559-65). All participants in FREEDOM-2 had been on metformin greater than or equal to 1,500 mg daily and had HbA1c greater than or equal to 7.5%.

©Boarding1Now/Thinkstock

“The continuous subcutaneous delivery of exenatide with ICTA 650 is a novel approach to improve glycemic control, ensuring adherence and consistent delivery of therapy for 6-12 months for people with type 2 diabetes,” Dr. Rosenstock said. The ICTA recipients first received a dose of 20 μg of exenatide daily for the first 12 weeks, then had that increased to 60 μg for the remainder of the study.

After 1 year, average reduction in HbA1c was 1.5% with ITCA 650 vs. 0.8% with sitagliptin, Dr. Rosenstock said. Sixty-one percent of those in the ITCA 650 group achieved greater than 0.5% reductions in HbA1c and more than 2 kg loss in body weight after a year, compared with 28% of the sitagliptin group.

Overall, the patients who receive the ITCA 650 achieved an average body weight reduction of 4 kg vs. 1.3 kg for the sitagliptin patients. Again, 61% of the ITCA patients achieved target HbA1c of less than 7% vs. 42% of the sitagliptin group. Rescue therapy was required in 15% with ITCA 650 and 35% with sitagliptin, and minor hypoglycemia occurred in 4.2% with ITCA 650 vs. 1.9% with sitagliptin.

The ICTA 650 group did have a higher incidence of adverse events, Dr. Rosenstock said, 82% vs. 74%. These included side effects at the application site like hematoma, bleeding, infection, or pain, as well as gastrointestinal (GI) problems such as nausea and vomiting. “The GI adverse events were similar to what we have seen with other GLP-1 receptor agonists,” Dr. Rosenstock said. “The incidence of nausea spiked at the initial insertion and then when we increased the dose from 20 μg to 60 μg, but the second time the ICTA 650 was replaced for 60 μg dosing, the nausea rates did not spike.” The ICTA 650 group had a discontinuation rate of 1%.

Each mini-pump inserted in the FREEDOM-2 trial had a duration of 6 months, but Dr. Rosenstock said the goal is to achieve extended-release dosing with a single mini-pump for 2 years.

Dr. Rosenstock disclosed he serves on the advisory panels of Boehringer Ingelheim Pharmaceuticals, Daiichi-Sankyo Co., Eli Lilly and Company, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, MannKind Corporation, Merck & Co., Novartis, Novo Nordisk, Sanofi U.S., and Takeda Pharmaceutical Company; and that he has received research support from Amylin Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, MannKind Corporation, Merck & Co., Novartis, Novo Nordisk, Pfizer, Roche Pharmaceuticals, Sanofi U.S. and Takeda.

Copenhagen – Among older adults with acute myeloid leukemia, the combination of a drug-antibody conjugate and hypomethylating therapy was associated with high complete remission rates.

In a phase I study of 53 patients (median age 75 years) with AML, the combination of vadastuximab talirine and a hypomethylating agent (HMA), either azacitidine or decitabine, was associated in 49 efficacy-evaluable patients with a 71% rate of composite complete remission (CR) and complete remission with incomplete recovery of counts (CRi), reported Dr. Amir Fathi from the Massachusetts General Hospital Cancer Center in Boston.

“This high remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone,” he said at a briefing at the annual congress of the European Hematology Association.

Many older patients with AML may not be able to withstand the rigors of cytotoxic chemotherapy, and these patients are often treated with hypomethylating agents or other low-intensity therapies, Dr. Fathi said.

Vadastuximab talirine is an antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells, and in preclinical studies has been shown to enhance the cytotoxic effects of HMAs when given in combination.

Dr. Fathi reported preliminary data on 53 patients enrolled in a phase 1 study of the safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab in combination with an HMA.

Neil Osterweil/Frontline Medical News

They enrolled adults with good performance status (Eastern Cooperative Oncology Group 0 or 1) who had CD33-positive AML and had declined intensive chemotherapy. They were given vadastuximab 10 mg/kg in an outpatient intravenous basis every 4 weeks on the fifth day of a 5-day HMA regimen,

Patients who were observed to have a clinical benefit could continue on treatment until relapse or unacceptable toxicity.

Of the 53 patients enrolled, 19 had adverse cytogenetic risk, and 30 had intermediate risk. The majority of patients (48) had not previously been treated for AML, and 5 had received prior low-intensity therapy for the myelodysplastic syndrome.

A total of 49 patients had sufficient data for the efficacy evaluation, and among these patients the composite CR/CRi rate was 71%; the rates of CR/CRi were similar whether the partner HMA was azacitadine or decitabine.

The overall response rate was 76%, with responses seem among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

In addition, 8 of 19 patients with a CR, and 5 of 15 with a CRi met the definition for minimal residual disease.

Dr. Fathi reported early overall survival results, which he noted were still evolving. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months after a median follow-up of 12.58 months.

The median relapse free-survival was 7.7 months. As of last follow-up, 27 patients were alive and remained on study.

The 30-day mortality rate was 2%, and the 60-day rate was 8%.

The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue, thrombocytopenia, nausea, febrile neutropenia, constipation, and anemia

The most common grade 3 or greater treatment-emergent adverse events were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.

In an interview, Dr. Fathi said that he has been very encouraged by the results thus far.

“This is a traditionally high-risk patient population. Even with a conventional induction cytotoxic chemotherapy, rates of remission in this population are relatively lower, so if the remission rates pan out in a larger population, I would say it competes and possibly supersedes what you would expect in an older population,” Dr. Fathi said.

Asked whether it might be possible to boost outcomes further with additional therapies, he said that “I’m not sure if there is much more improvement over what we are already seeing; a rate of 70-something percent among older adults with AML is quite good.”

“I like this ‘Trojan-horse’ approach to treating AML,” commented Dr. Anton Hagenbeek, professor of hematology at the Academic Medical Center, University of Amsterdam, who moderated the briefing.

A randomized phase III trial of vadastuximab talirine and HMA therapy is currently enrolling patients.

The study was funded by Seattle Genetics. Dr. Fathi reported no relevant disclosures.

Copenhagen – Among older adults with acute myeloid leukemia, the combination of a drug-antibody conjugate and hypomethylating therapy was associated with high complete remission rates.

In a phase I study of 53 patients (median age 75 years) with AML, the combination of vadastuximab talirine and a hypomethylating agent (HMA), either azacitidine or decitabine, was associated in 49 efficacy-evaluable patients with a 71% rate of composite complete remission (CR) and complete remission with incomplete recovery of counts (CRi), reported Dr. Amir Fathi from the Massachusetts General Hospital Cancer Center in Boston.

“This high remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone,” he said at a briefing at the annual congress of the European Hematology Association.

Many older patients with AML may not be able to withstand the rigors of cytotoxic chemotherapy, and these patients are often treated with hypomethylating agents or other low-intensity therapies, Dr. Fathi said.

Vadastuximab talirine is an antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells, and in preclinical studies has been shown to enhance the cytotoxic effects of HMAs when given in combination.

Dr. Fathi reported preliminary data on 53 patients enrolled in a phase 1 study of the safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab in combination with an HMA.

Neil Osterweil/Frontline Medical News

They enrolled adults with good performance status (Eastern Cooperative Oncology Group 0 or 1) who had CD33-positive AML and had declined intensive chemotherapy. They were given vadastuximab 10 mg/kg in an outpatient intravenous basis every 4 weeks on the fifth day of a 5-day HMA regimen,

Patients who were observed to have a clinical benefit could continue on treatment until relapse or unacceptable toxicity.

Of the 53 patients enrolled, 19 had adverse cytogenetic risk, and 30 had intermediate risk. The majority of patients (48) had not previously been treated for AML, and 5 had received prior low-intensity therapy for the myelodysplastic syndrome.

A total of 49 patients had sufficient data for the efficacy evaluation, and among these patients the composite CR/CRi rate was 71%; the rates of CR/CRi were similar whether the partner HMA was azacitadine or decitabine.

The overall response rate was 76%, with responses seem among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

In addition, 8 of 19 patients with a CR, and 5 of 15 with a CRi met the definition for minimal residual disease.

Dr. Fathi reported early overall survival results, which he noted were still evolving. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months after a median follow-up of 12.58 months.

The median relapse free-survival was 7.7 months. As of last follow-up, 27 patients were alive and remained on study.

The 30-day mortality rate was 2%, and the 60-day rate was 8%.

The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue, thrombocytopenia, nausea, febrile neutropenia, constipation, and anemia

The most common grade 3 or greater treatment-emergent adverse events were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.

In an interview, Dr. Fathi said that he has been very encouraged by the results thus far.

“This is a traditionally high-risk patient population. Even with a conventional induction cytotoxic chemotherapy, rates of remission in this population are relatively lower, so if the remission rates pan out in a larger population, I would say it competes and possibly supersedes what you would expect in an older population,” Dr. Fathi said.

Asked whether it might be possible to boost outcomes further with additional therapies, he said that “I’m not sure if there is much more improvement over what we are already seeing; a rate of 70-something percent among older adults with AML is quite good.”

“I like this ‘Trojan-horse’ approach to treating AML,” commented Dr. Anton Hagenbeek, professor of hematology at the Academic Medical Center, University of Amsterdam, who moderated the briefing.

A randomized phase III trial of vadastuximab talirine and HMA therapy is currently enrolling patients.

The study was funded by Seattle Genetics. Dr. Fathi reported no relevant disclosures.

Copenhagen – Among older adults with acute myeloid leukemia, the combination of a drug-antibody conjugate and hypomethylating therapy was associated with high complete remission rates.

In a phase I study of 53 patients (median age 75 years) with AML, the combination of vadastuximab talirine and a hypomethylating agent (HMA), either azacitidine or decitabine, was associated in 49 efficacy-evaluable patients with a 71% rate of composite complete remission (CR) and complete remission with incomplete recovery of counts (CRi), reported Dr. Amir Fathi from the Massachusetts General Hospital Cancer Center in Boston.

“This high remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone,” he said at a briefing at the annual congress of the European Hematology Association.

Many older patients with AML may not be able to withstand the rigors of cytotoxic chemotherapy, and these patients are often treated with hypomethylating agents or other low-intensity therapies, Dr. Fathi said.

Vadastuximab talirine is an antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells, and in preclinical studies has been shown to enhance the cytotoxic effects of HMAs when given in combination.

Dr. Fathi reported preliminary data on 53 patients enrolled in a phase 1 study of the safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab in combination with an HMA.

Neil Osterweil/Frontline Medical News

They enrolled adults with good performance status (Eastern Cooperative Oncology Group 0 or 1) who had CD33-positive AML and had declined intensive chemotherapy. They were given vadastuximab 10 mg/kg in an outpatient intravenous basis every 4 weeks on the fifth day of a 5-day HMA regimen,

Patients who were observed to have a clinical benefit could continue on treatment until relapse or unacceptable toxicity.

Of the 53 patients enrolled, 19 had adverse cytogenetic risk, and 30 had intermediate risk. The majority of patients (48) had not previously been treated for AML, and 5 had received prior low-intensity therapy for the myelodysplastic syndrome.

A total of 49 patients had sufficient data for the efficacy evaluation, and among these patients the composite CR/CRi rate was 71%; the rates of CR/CRi were similar whether the partner HMA was azacitadine or decitabine.

The overall response rate was 76%, with responses seem among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

In addition, 8 of 19 patients with a CR, and 5 of 15 with a CRi met the definition for minimal residual disease.

Dr. Fathi reported early overall survival results, which he noted were still evolving. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months after a median follow-up of 12.58 months.

The median relapse free-survival was 7.7 months. As of last follow-up, 27 patients were alive and remained on study.

The 30-day mortality rate was 2%, and the 60-day rate was 8%.

The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue, thrombocytopenia, nausea, febrile neutropenia, constipation, and anemia

The most common grade 3 or greater treatment-emergent adverse events were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.

In an interview, Dr. Fathi said that he has been very encouraged by the results thus far.

“This is a traditionally high-risk patient population. Even with a conventional induction cytotoxic chemotherapy, rates of remission in this population are relatively lower, so if the remission rates pan out in a larger population, I would say it competes and possibly supersedes what you would expect in an older population,” Dr. Fathi said.

Asked whether it might be possible to boost outcomes further with additional therapies, he said that “I’m not sure if there is much more improvement over what we are already seeing; a rate of 70-something percent among older adults with AML is quite good.”

“I like this ‘Trojan-horse’ approach to treating AML,” commented Dr. Anton Hagenbeek, professor of hematology at the Academic Medical Center, University of Amsterdam, who moderated the briefing.

A randomized phase III trial of vadastuximab talirine and HMA therapy is currently enrolling patients.

The study was funded by Seattle Genetics. Dr. Fathi reported no relevant disclosures.

Copenhagen – The experimental antibody-drug conjugate inotuzumab ozogamicin was associated with a nearly threefold higher complete remission rate than standard intensive chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia, investigators reported.

Among 218 patients in a phase III clinical trial, rates of combined complete remissions (CR) and complete remission with incomplete recovery of counts (CRi) were 80.7% for patients randomly assigned to receive the anti-CD22 conjugated antibody inotuzumab ozogamicin, compared with 29.4% for patients assigned to receive a standard intensive chemotherapy regimen chosen by investigators (P less than .001).

In addition, among patients who had complete remissions in both groups, significantly more patients in the inotuzumab ozogamicin group had fewer than .01% marrow blasts, a level below the threshold for minimal residual disease (MRD) (78.4% vs. 28.1%, respectively, P less than .001), reported Dr. Hagop Kantarjian, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies targeting CD19,” he said at the annual congress of the European Hematology Association.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic.  CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Dr. Daniel DeAngelo from the Dana-Farber Cancer Institute in Boston reported that in the same cohort of patients, the first 218 of 326 randomized in the INO-VATE trial, , the co-primary endpoint of CR/CRi by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care.The updated data presented at the meeting also are published online in the New England Journal of Medicine 2016 June doi:10.1056/NEJMoa1509277 .

The phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or standard of care, consisting of either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m²/cycle and was reduced to 1.5 mg/m²/cycle once a CR or CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients who refused to start treatment, all in the standard-of-care arm.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were in salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Dr. Kantarjian reported that in addition to the superior remission rates seen with inotuzumab ozogamicin, patients on the antibody-drug conjugate had significantly longer duration of remissions, at a median of 4.6 months vs. 3.1 months for patients on chemotherapy (P = .003).

An intention-to-treat survival analysis including all 326 patients randomized in the trial showed that progression-free survival was significantly longer in the inotuzumab ozogamicin group, at a median of 5.0 vs. 1.8 months (hazard ratio .45 P less than .001).

Neil Osterweil/Frontline Medical News

Overall survival was slightly better with inotuzumab, at a median of 7.7 months vs. 6.7 months, but this did not meet the study definition of significantly improved overall survival with a pre-specified boundary of P = .014 or lower.

In the safety population, which included 139 patients assigned to inotuzumab and 120 to chemotherapy who had received at least one dose of the assigned regimen before data cutoff, the most frequent grade 3 or higher non-hematologic adverse events with inotuzumab ozogamicin were liver-related. In all, 13% of patients assigned to inotuzumab in the safety population developed veno-occlusive liver disease of any grade, compared with 1% of those assigned to standard of care.

“This drug showed consistently high activity in several studies, so I think it’s very exciting, The real challenge will be how to proceed, how to incorporate it into clinical trials both in pediatrics and adults,” commented Dr. Shai Izraeli, head of the section of functional genomics and childhood leukemia and cancer research at Sheba Medical Center in Ramat Gan, Israel. Dr. Izraeli was co-moderator of the late-breaking abstract session where the data were presented, but was not involved in the study.

He said in an interview that the challenge for investigators will be to develop clinical trials that combine this agent with different immunotherapies from different companies, which would be a logistical nightmare, “but I think we need to do it.”

The study was funded by Pfizer. Dr. Kantarjian disclosed research support from the company. Dr. Izraeli reported having no relevant disclosures.

Copenhagen – The experimental antibody-drug conjugate inotuzumab ozogamicin was associated with a nearly threefold higher complete remission rate than standard intensive chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia, investigators reported.

Among 218 patients in a phase III clinical trial, rates of combined complete remissions (CR) and complete remission with incomplete recovery of counts (CRi) were 80.7% for patients randomly assigned to receive the anti-CD22 conjugated antibody inotuzumab ozogamicin, compared with 29.4% for patients assigned to receive a standard intensive chemotherapy regimen chosen by investigators (P less than .001).

In addition, among patients who had complete remissions in both groups, significantly more patients in the inotuzumab ozogamicin group had fewer than .01% marrow blasts, a level below the threshold for minimal residual disease (MRD) (78.4% vs. 28.1%, respectively, P less than .001), reported Dr. Hagop Kantarjian, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies targeting CD19,” he said at the annual congress of the European Hematology Association.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic.  CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Dr. Daniel DeAngelo from the Dana-Farber Cancer Institute in Boston reported that in the same cohort of patients, the first 218 of 326 randomized in the INO-VATE trial, , the co-primary endpoint of CR/CRi by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care.The updated data presented at the meeting also are published online in the New England Journal of Medicine 2016 June doi:10.1056/NEJMoa1509277 .

The phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or standard of care, consisting of either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m²/cycle and was reduced to 1.5 mg/m²/cycle once a CR or CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients who refused to start treatment, all in the standard-of-care arm.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were in salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Dr. Kantarjian reported that in addition to the superior remission rates seen with inotuzumab ozogamicin, patients on the antibody-drug conjugate had significantly longer duration of remissions, at a median of 4.6 months vs. 3.1 months for patients on chemotherapy (P = .003).

An intention-to-treat survival analysis including all 326 patients randomized in the trial showed that progression-free survival was significantly longer in the inotuzumab ozogamicin group, at a median of 5.0 vs. 1.8 months (hazard ratio .45 P less than .001).

Neil Osterweil/Frontline Medical News

Overall survival was slightly better with inotuzumab, at a median of 7.7 months vs. 6.7 months, but this did not meet the study definition of significantly improved overall survival with a pre-specified boundary of P = .014 or lower.

In the safety population, which included 139 patients assigned to inotuzumab and 120 to chemotherapy who had received at least one dose of the assigned regimen before data cutoff, the most frequent grade 3 or higher non-hematologic adverse events with inotuzumab ozogamicin were liver-related. In all, 13% of patients assigned to inotuzumab in the safety population developed veno-occlusive liver disease of any grade, compared with 1% of those assigned to standard of care.

“This drug showed consistently high activity in several studies, so I think it’s very exciting, The real challenge will be how to proceed, how to incorporate it into clinical trials both in pediatrics and adults,” commented Dr. Shai Izraeli, head of the section of functional genomics and childhood leukemia and cancer research at Sheba Medical Center in Ramat Gan, Israel. Dr. Izraeli was co-moderator of the late-breaking abstract session where the data were presented, but was not involved in the study.

He said in an interview that the challenge for investigators will be to develop clinical trials that combine this agent with different immunotherapies from different companies, which would be a logistical nightmare, “but I think we need to do it.”

The study was funded by Pfizer. Dr. Kantarjian disclosed research support from the company. Dr. Izraeli reported having no relevant disclosures.

Copenhagen – The experimental antibody-drug conjugate inotuzumab ozogamicin was associated with a nearly threefold higher complete remission rate than standard intensive chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia, investigators reported.

Among 218 patients in a phase III clinical trial, rates of combined complete remissions (CR) and complete remission with incomplete recovery of counts (CRi) were 80.7% for patients randomly assigned to receive the anti-CD22 conjugated antibody inotuzumab ozogamicin, compared with 29.4% for patients assigned to receive a standard intensive chemotherapy regimen chosen by investigators (P less than .001).

In addition, among patients who had complete remissions in both groups, significantly more patients in the inotuzumab ozogamicin group had fewer than .01% marrow blasts, a level below the threshold for minimal residual disease (MRD) (78.4% vs. 28.1%, respectively, P less than .001), reported Dr. Hagop Kantarjian, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies targeting CD19,” he said at the annual congress of the European Hematology Association.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic.  CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Dr. Daniel DeAngelo from the Dana-Farber Cancer Institute in Boston reported that in the same cohort of patients, the first 218 of 326 randomized in the INO-VATE trial, , the co-primary endpoint of CR/CRi by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care.The updated data presented at the meeting also are published online in the New England Journal of Medicine 2016 June doi:10.1056/NEJMoa1509277 .

The phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or standard of care, consisting of either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m²/cycle and was reduced to 1.5 mg/m²/cycle once a CR or CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients who refused to start treatment, all in the standard-of-care arm.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were in salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Dr. Kantarjian reported that in addition to the superior remission rates seen with inotuzumab ozogamicin, patients on the antibody-drug conjugate had significantly longer duration of remissions, at a median of 4.6 months vs. 3.1 months for patients on chemotherapy (P = .003).

An intention-to-treat survival analysis including all 326 patients randomized in the trial showed that progression-free survival was significantly longer in the inotuzumab ozogamicin group, at a median of 5.0 vs. 1.8 months (hazard ratio .45 P less than .001).

Neil Osterweil/Frontline Medical News

Overall survival was slightly better with inotuzumab, at a median of 7.7 months vs. 6.7 months, but this did not meet the study definition of significantly improved overall survival with a pre-specified boundary of P = .014 or lower.

In the safety population, which included 139 patients assigned to inotuzumab and 120 to chemotherapy who had received at least one dose of the assigned regimen before data cutoff, the most frequent grade 3 or higher non-hematologic adverse events with inotuzumab ozogamicin were liver-related. In all, 13% of patients assigned to inotuzumab in the safety population developed veno-occlusive liver disease of any grade, compared with 1% of those assigned to standard of care.

“This drug showed consistently high activity in several studies, so I think it’s very exciting, The real challenge will be how to proceed, how to incorporate it into clinical trials both in pediatrics and adults,” commented Dr. Shai Izraeli, head of the section of functional genomics and childhood leukemia and cancer research at Sheba Medical Center in Ramat Gan, Israel. Dr. Izraeli was co-moderator of the late-breaking abstract session where the data were presented, but was not involved in the study.

He said in an interview that the challenge for investigators will be to develop clinical trials that combine this agent with different immunotherapies from different companies, which would be a logistical nightmare, “but I think we need to do it.”

The study was funded by Pfizer. Dr. Kantarjian disclosed research support from the company. Dr. Izraeli reported having no relevant disclosures.

Chicago – Survivors of childhood cancers face several later risks from treatment, and investigators presented studies evaluating risks in three specific areas – secondary neoplasms, premature menopause, and neurocognitive function – at the annual meeting of the American Society of Clinical Oncology.

Discussant Paul Nathan, M.D., of The Hospital for Sick Children in Toronto, said “the whole purpose” of research in this area “is to start to understand the predictors and modifiers of late effects” and then to design risk assessment tools and interventions to reduce long-term toxicity. These interventions include modification of chemotherapy and radiation doses, protective strategies, and disease risk stratification to adjust intensity of therapies.

Other strategies are to use behavioral interventions directed at improving compliance with follow-up to detect problems earlier and the use of real-time monitoring, such as with smart phones or fitness trackers. He said one limitation of this sort of research and implementing interventions to reduce late toxicities is that “you need time to document long-term outcomes.” So tracking newer therapies, such as proton beam radiation, small molecule drugs, and immunotherapy, is “going to take time, perhaps decades, before you understand their impact on patients.”

Risk of secondary neoplasms reduced

Risk-stratifying of disease “has allowed us to make attempts to minimize late effects by modifying therapy over time in certain subgroups of lower-risk patients,” said Dr. Lucie Turcotte of the University of Minnesota in Minneapolis.

To study the effects of these changes, she determined the risk of certain subsequent malignant or benign neoplasms over three periods of therapeutic exposure among 23,603 5-year survivors of childhood cancers diagnosed at less than 21 years of age from 1970 to 1999, drawing from the cohort of the Childhood Cancer Survivor Study (CCSS). The CCSS represents about 20% of childhood cancer survivors in the United States for the study period.

Over the decades of 1970-1979, 1980-1989, and 1990-1999, the use of any radiation went from 77% to 58% to 41%, respectively. Cranial radiation for acute lymphoblastic leukemia (ALL) decreased from 85% to 19%, abdominal radiation for Wilms tumor from 78% to 43%, and chest radiotherapy for Hodgkin lymphoma from 87% to 61%. The proportion of children receiving alkylating agents, anthracyclines, and epipodophyllotoxins went up, but the cumulative doses went down (N Engl J Med. 2016 Mar 3;374(9):833-42).

Dr. Nathan said today, almost no child gets cranial radiation for ALL. “So we’ve slowly learned that our treatments are toxic, and we’ve certainly done what we can to change them.”

But have these changes made a difference? Dr. Turcotte found that survivors remain at increased risk of a secondary neoplasm, but the risk was lower for children treated in later time periods.

Dr. Nathan pointed to Dr. Turcotte’s data showing that the incidence of subsequent malignant neoplasms decreased from 1970 to 1999 by 7% for each 5-year era (15-year risk: 2.3% to 1.6%; P = .001; number needed to treat, NNT = 143). Similarly, non-melanoma skin cancer 15-year risk decreased from 0.7% to 0.1% (P less than .001; NNT = 167). The NNT’s are “certainly important, but these are not major differences over time,” Dr. Nathan said. Knowing the impact of newer, targeted therapeutic approaches will take some time.

Predicting risk of premature menopause

Also using the CCSS data, Dr. Jennifer Levine of Columbia University Medical Center, New York, N.Y., studied the prevalence of and risk factors for nonsurgical premature menopause (NSPM), defined as cessation of menses prior to age 40 years, as well as the effect on reproductive outcomes for survivors of childhood cancers.

Dr. Nathan said when a child is first diagnosed with cancer, seldom does the issue of fertility come up early in the discussion, “but when you treat young adults who are survivors, the number one thing they talk about often is fertility. And so doing a better job in predicting who is at risk for infertility is clearly a priority for survivorship research.”

He said the development of the cyclophosphamide equivalent dose (CED) by D.M Green et al. (Pediatr Blood Cancer. 2014 Jan;61(1):53-67) has been very helpful for quantifying alkylating agent exposure to make comparisons between studies. The goal is to develop a risk assessment tool to be able to tell patients and families their fertility risk based on demographics, therapy, and biomarkers.

Being able to evaluate risk is critically important because for girls, oocyte or ovarian harvesting or even transvaginal ultrasound is highly invasive, and these procedures should be recommended only if their risk for infertility is very high.

Dr. Levine studied 2,930 female cancer survivors diagnosed at a median age of 6 years between 1979 and 1986 and a median age at follow-up of 34 years, who were compared with 1,399 healthy siblings. Of the survivor cohort, 110 developed NSPM at a median age of 32 years, and the prevalence of NSPM at age 40 years for the entire cohort was 9.1%, giving a relative risk of NSPM of 10.5 compared with siblings, who had a 0.9% NSPM prevalence at age 40.

She found that exposure to alkylating agents and older age at diagnosis put childhood cancer survivors at increased risk of NSPM, which was associated with lower rates of pregnancy and live births after age 31 years. The greatest risk of NSPM occurred if the cyclophosphamide equivalent dose was greater than 6000 mg/m² (odds ratio = 3.6 compared with no CED); if there had been any radiation to the ovaries (less than 5 Gy: OR = 4.0; 5 Gy or more: OR = 20.4); or if the age at diagnosis was greater than 14 years (OR = 2.3).

Women with NSPM, compared with survivors without NSPM, were less likely ever to be pregnant (OR = 0.41) or to have a live birth after age 30 (OR = 0.35). However, these outcomes were no different between the ages of 21 and 30. Dr. Levine said this information can assist clinicians in counseling their patients about the risk for early menopause and planning for alternative reproductive means, such as oocyte or embryo harvesting and preservation.

Neurocognitive functioning after treatment

Dr. Wei Liu of St. Jude Children’s Research Hospital, Memphis, Tenn., studied the neurocognitive function of long-term survivors of ALL.

Dr. Nathan called ALL “the paradigm for how we’ve sort of learned and adjusted how we treat patients based on late effects.” Early on, the disease was treated with craniospinal radiation and intrathecal chemotherapy, and while patients survived, it became obvious that they suffered neurocognitive and endocrine problems, growth abnormalities, and secondary malignancies. These findings forced a reevaluatuon of treatments, leading to elimination of spinal radiation, reduction of cranial radiation dose, intensification of systemic therapy, including methotrexate, and risk stratification allowing modification of therapies.

Survival was sustained, but long-term outcomes were still based on children treated with radiation. So long-term cognitive consequences in the more modern era of therapy were unknown. Only recently have adult cohorts become available who were treated in the chemotherapy-only era.

Dr. Liu studied 159 ALL survivors who had been treated with chemotherapy alone at a mean age of 9.2 years. The follow-up was at a median of 7.6 years off therapy at a mean age of 13.7 years. At the end of the chemotherapy protocol, patients completed tests of sustained attention, and parents rated survivors’ behavior on standard scales.

She found that for these childhood cancer survivors, sustained attention and behavior functioning at the end of chemotherapy predicted long-term attention and processing speed outcomes. Only exposure to chemotherapy, and not end-of-therapy function, predicted that survivors would have poor executive function of fluency and flexibility at long-term follow up.

Dr. Nathan praised the investigators for their foresight to collect data on the methotrexate area under the curve, number of triple intrathecal therapies (cytarabine, methotrexate, and hydrocortisone), and neurocognitive functioning at the end of chemotherapy. “What’s clear is that chemotherapy alone can lead to neurocognitive late effects,” he said. “But what’s also important is that not all late effects can be predicted by end of therapy assessments.” These late effects appear to evolve over time, so ongoing assessments are needed.

Dr. Turcotte, Dr. Liu, Dr. Levine, and Dr. Nathan each reported no financial disclosures.

Chicago – Survivors of childhood cancers face several later risks from treatment, and investigators presented studies evaluating risks in three specific areas – secondary neoplasms, premature menopause, and neurocognitive function – at the annual meeting of the American Society of Clinical Oncology.

Discussant Paul Nathan, M.D., of The Hospital for Sick Children in Toronto, said “the whole purpose” of research in this area “is to start to understand the predictors and modifiers of late effects” and then to design risk assessment tools and interventions to reduce long-term toxicity. These interventions include modification of chemotherapy and radiation doses, protective strategies, and disease risk stratification to adjust intensity of therapies.

Other strategies are to use behavioral interventions directed at improving compliance with follow-up to detect problems earlier and the use of real-time monitoring, such as with smart phones or fitness trackers. He said one limitation of this sort of research and implementing interventions to reduce late toxicities is that “you need time to document long-term outcomes.” So tracking newer therapies, such as proton beam radiation, small molecule drugs, and immunotherapy, is “going to take time, perhaps decades, before you understand their impact on patients.”

Risk of secondary neoplasms reduced

Risk-stratifying of disease “has allowed us to make attempts to minimize late effects by modifying therapy over time in certain subgroups of lower-risk patients,” said Dr. Lucie Turcotte of the University of Minnesota in Minneapolis.

To study the effects of these changes, she determined the risk of certain subsequent malignant or benign neoplasms over three periods of therapeutic exposure among 23,603 5-year survivors of childhood cancers diagnosed at less than 21 years of age from 1970 to 1999, drawing from the cohort of the Childhood Cancer Survivor Study (CCSS). The CCSS represents about 20% of childhood cancer survivors in the United States for the study period.

Over the decades of 1970-1979, 1980-1989, and 1990-1999, the use of any radiation went from 77% to 58% to 41%, respectively. Cranial radiation for acute lymphoblastic leukemia (ALL) decreased from 85% to 19%, abdominal radiation for Wilms tumor from 78% to 43%, and chest radiotherapy for Hodgkin lymphoma from 87% to 61%. The proportion of children receiving alkylating agents, anthracyclines, and epipodophyllotoxins went up, but the cumulative doses went down (N Engl J Med. 2016 Mar 3;374(9):833-42).

Dr. Nathan said today, almost no child gets cranial radiation for ALL. “So we’ve slowly learned that our treatments are toxic, and we’ve certainly done what we can to change them.”

But have these changes made a difference? Dr. Turcotte found that survivors remain at increased risk of a secondary neoplasm, but the risk was lower for children treated in later time periods.

Dr. Nathan pointed to Dr. Turcotte’s data showing that the incidence of subsequent malignant neoplasms decreased from 1970 to 1999 by 7% for each 5-year era (15-year risk: 2.3% to 1.6%; P = .001; number needed to treat, NNT = 143). Similarly, non-melanoma skin cancer 15-year risk decreased from 0.7% to 0.1% (P less than .001; NNT = 167). The NNT’s are “certainly important, but these are not major differences over time,” Dr. Nathan said. Knowing the impact of newer, targeted therapeutic approaches will take some time.

Predicting risk of premature menopause

Also using the CCSS data, Dr. Jennifer Levine of Columbia University Medical Center, New York, N.Y., studied the prevalence of and risk factors for nonsurgical premature menopause (NSPM), defined as cessation of menses prior to age 40 years, as well as the effect on reproductive outcomes for survivors of childhood cancers.

Dr. Nathan said when a child is first diagnosed with cancer, seldom does the issue of fertility come up early in the discussion, “but when you treat young adults who are survivors, the number one thing they talk about often is fertility. And so doing a better job in predicting who is at risk for infertility is clearly a priority for survivorship research.”

He said the development of the cyclophosphamide equivalent dose (CED) by D.M Green et al. (Pediatr Blood Cancer. 2014 Jan;61(1):53-67) has been very helpful for quantifying alkylating agent exposure to make comparisons between studies. The goal is to develop a risk assessment tool to be able to tell patients and families their fertility risk based on demographics, therapy, and biomarkers.

Being able to evaluate risk is critically important because for girls, oocyte or ovarian harvesting or even transvaginal ultrasound is highly invasive, and these procedures should be recommended only if their risk for infertility is very high.

Dr. Levine studied 2,930 female cancer survivors diagnosed at a median age of 6 years between 1979 and 1986 and a median age at follow-up of 34 years, who were compared with 1,399 healthy siblings. Of the survivor cohort, 110 developed NSPM at a median age of 32 years, and the prevalence of NSPM at age 40 years for the entire cohort was 9.1%, giving a relative risk of NSPM of 10.5 compared with siblings, who had a 0.9% NSPM prevalence at age 40.

She found that exposure to alkylating agents and older age at diagnosis put childhood cancer survivors at increased risk of NSPM, which was associated with lower rates of pregnancy and live births after age 31 years. The greatest risk of NSPM occurred if the cyclophosphamide equivalent dose was greater than 6000 mg/m² (odds ratio = 3.6 compared with no CED); if there had been any radiation to the ovaries (less than 5 Gy: OR = 4.0; 5 Gy or more: OR = 20.4); or if the age at diagnosis was greater than 14 years (OR = 2.3).

Women with NSPM, compared with survivors without NSPM, were less likely ever to be pregnant (OR = 0.41) or to have a live birth after age 30 (OR = 0.35). However, these outcomes were no different between the ages of 21 and 30. Dr. Levine said this information can assist clinicians in counseling their patients about the risk for early menopause and planning for alternative reproductive means, such as oocyte or embryo harvesting and preservation.

Neurocognitive functioning after treatment

Dr. Wei Liu of St. Jude Children’s Research Hospital, Memphis, Tenn., studied the neurocognitive function of long-term survivors of ALL.

Dr. Nathan called ALL “the paradigm for how we’ve sort of learned and adjusted how we treat patients based on late effects.” Early on, the disease was treated with craniospinal radiation and intrathecal chemotherapy, and while patients survived, it became obvious that they suffered neurocognitive and endocrine problems, growth abnormalities, and secondary malignancies. These findings forced a reevaluatuon of treatments, leading to elimination of spinal radiation, reduction of cranial radiation dose, intensification of systemic therapy, including methotrexate, and risk stratification allowing modification of therapies.

Survival was sustained, but long-term outcomes were still based on children treated with radiation. So long-term cognitive consequences in the more modern era of therapy were unknown. Only recently have adult cohorts become available who were treated in the chemotherapy-only era.

Dr. Liu studied 159 ALL survivors who had been treated with chemotherapy alone at a mean age of 9.2 years. The follow-up was at a median of 7.6 years off therapy at a mean age of 13.7 years. At the end of the chemotherapy protocol, patients completed tests of sustained attention, and parents rated survivors’ behavior on standard scales.

She found that for these childhood cancer survivors, sustained attention and behavior functioning at the end of chemotherapy predicted long-term attention and processing speed outcomes. Only exposure to chemotherapy, and not end-of-therapy function, predicted that survivors would have poor executive function of fluency and flexibility at long-term follow up.

Dr. Nathan praised the investigators for their foresight to collect data on the methotrexate area under the curve, number of triple intrathecal therapies (cytarabine, methotrexate, and hydrocortisone), and neurocognitive functioning at the end of chemotherapy. “What’s clear is that chemotherapy alone can lead to neurocognitive late effects,” he said. “But what’s also important is that not all late effects can be predicted by end of therapy assessments.” These late effects appear to evolve over time, so ongoing assessments are needed.

Dr. Turcotte, Dr. Liu, Dr. Levine, and Dr. Nathan each reported no financial disclosures.

Chicago – Survivors of childhood cancers face several later risks from treatment, and investigators presented studies evaluating risks in three specific areas – secondary neoplasms, premature menopause, and neurocognitive function – at the annual meeting of the American Society of Clinical Oncology.

Discussant Paul Nathan, M.D., of The Hospital for Sick Children in Toronto, said “the whole purpose” of research in this area “is to start to understand the predictors and modifiers of late effects” and then to design risk assessment tools and interventions to reduce long-term toxicity. These interventions include modification of chemotherapy and radiation doses, protective strategies, and disease risk stratification to adjust intensity of therapies.

Other strategies are to use behavioral interventions directed at improving compliance with follow-up to detect problems earlier and the use of real-time monitoring, such as with smart phones or fitness trackers. He said one limitation of this sort of research and implementing interventions to reduce late toxicities is that “you need time to document long-term outcomes.” So tracking newer therapies, such as proton beam radiation, small molecule drugs, and immunotherapy, is “going to take time, perhaps decades, before you understand their impact on patients.”

Risk of secondary neoplasms reduced

Risk-stratifying of disease “has allowed us to make attempts to minimize late effects by modifying therapy over time in certain subgroups of lower-risk patients,” said Dr. Lucie Turcotte of the University of Minnesota in Minneapolis.

To study the effects of these changes, she determined the risk of certain subsequent malignant or benign neoplasms over three periods of therapeutic exposure among 23,603 5-year survivors of childhood cancers diagnosed at less than 21 years of age from 1970 to 1999, drawing from the cohort of the Childhood Cancer Survivor Study (CCSS). The CCSS represents about 20% of childhood cancer survivors in the United States for the study period.

Over the decades of 1970-1979, 1980-1989, and 1990-1999, the use of any radiation went from 77% to 58% to 41%, respectively. Cranial radiation for acute lymphoblastic leukemia (ALL) decreased from 85% to 19%, abdominal radiation for Wilms tumor from 78% to 43%, and chest radiotherapy for Hodgkin lymphoma from 87% to 61%. The proportion of children receiving alkylating agents, anthracyclines, and epipodophyllotoxins went up, but the cumulative doses went down (N Engl J Med. 2016 Mar 3;374(9):833-42).

Dr. Nathan said today, almost no child gets cranial radiation for ALL. “So we’ve slowly learned that our treatments are toxic, and we’ve certainly done what we can to change them.”

But have these changes made a difference? Dr. Turcotte found that survivors remain at increased risk of a secondary neoplasm, but the risk was lower for children treated in later time periods.

Dr. Nathan pointed to Dr. Turcotte’s data showing that the incidence of subsequent malignant neoplasms decreased from 1970 to 1999 by 7% for each 5-year era (15-year risk: 2.3% to 1.6%; P = .001; number needed to treat, NNT = 143). Similarly, non-melanoma skin cancer 15-year risk decreased from 0.7% to 0.1% (P less than .001; NNT = 167). The NNT’s are “certainly important, but these are not major differences over time,” Dr. Nathan said. Knowing the impact of newer, targeted therapeutic approaches will take some time.

Predicting risk of premature menopause

Also using the CCSS data, Dr. Jennifer Levine of Columbia University Medical Center, New York, N.Y., studied the prevalence of and risk factors for nonsurgical premature menopause (NSPM), defined as cessation of menses prior to age 40 years, as well as the effect on reproductive outcomes for survivors of childhood cancers.

Dr. Nathan said when a child is first diagnosed with cancer, seldom does the issue of fertility come up early in the discussion, “but when you treat young adults who are survivors, the number one thing they talk about often is fertility. And so doing a better job in predicting who is at risk for infertility is clearly a priority for survivorship research.”

He said the development of the cyclophosphamide equivalent dose (CED) by D.M Green et al. (Pediatr Blood Cancer. 2014 Jan;61(1):53-67) has been very helpful for quantifying alkylating agent exposure to make comparisons between studies. The goal is to develop a risk assessment tool to be able to tell patients and families their fertility risk based on demographics, therapy, and biomarkers.

Being able to evaluate risk is critically important because for girls, oocyte or ovarian harvesting or even transvaginal ultrasound is highly invasive, and these procedures should be recommended only if their risk for infertility is very high.

Dr. Levine studied 2,930 female cancer survivors diagnosed at a median age of 6 years between 1979 and 1986 and a median age at follow-up of 34 years, who were compared with 1,399 healthy siblings. Of the survivor cohort, 110 developed NSPM at a median age of 32 years, and the prevalence of NSPM at age 40 years for the entire cohort was 9.1%, giving a relative risk of NSPM of 10.5 compared with siblings, who had a 0.9% NSPM prevalence at age 40.

She found that exposure to alkylating agents and older age at diagnosis put childhood cancer survivors at increased risk of NSPM, which was associated with lower rates of pregnancy and live births after age 31 years. The greatest risk of NSPM occurred if the cyclophosphamide equivalent dose was greater than 6000 mg/m² (odds ratio = 3.6 compared with no CED); if there had been any radiation to the ovaries (less than 5 Gy: OR = 4.0; 5 Gy or more: OR = 20.4); or if the age at diagnosis was greater than 14 years (OR = 2.3).

Women with NSPM, compared with survivors without NSPM, were less likely ever to be pregnant (OR = 0.41) or to have a live birth after age 30 (OR = 0.35). However, these outcomes were no different between the ages of 21 and 30. Dr. Levine said this information can assist clinicians in counseling their patients about the risk for early menopause and planning for alternative reproductive means, such as oocyte or embryo harvesting and preservation.

Neurocognitive functioning after treatment

Dr. Wei Liu of St. Jude Children’s Research Hospital, Memphis, Tenn., studied the neurocognitive function of long-term survivors of ALL.

Dr. Nathan called ALL “the paradigm for how we’ve sort of learned and adjusted how we treat patients based on late effects.” Early on, the disease was treated with craniospinal radiation and intrathecal chemotherapy, and while patients survived, it became obvious that they suffered neurocognitive and endocrine problems, growth abnormalities, and secondary malignancies. These findings forced a reevaluatuon of treatments, leading to elimination of spinal radiation, reduction of cranial radiation dose, intensification of systemic therapy, including methotrexate, and risk stratification allowing modification of therapies.

Survival was sustained, but long-term outcomes were still based on children treated with radiation. So long-term cognitive consequences in the more modern era of therapy were unknown. Only recently have adult cohorts become available who were treated in the chemotherapy-only era.

Dr. Liu studied 159 ALL survivors who had been treated with chemotherapy alone at a mean age of 9.2 years. The follow-up was at a median of 7.6 years off therapy at a mean age of 13.7 years. At the end of the chemotherapy protocol, patients completed tests of sustained attention, and parents rated survivors’ behavior on standard scales.

She found that for these childhood cancer survivors, sustained attention and behavior functioning at the end of chemotherapy predicted long-term attention and processing speed outcomes. Only exposure to chemotherapy, and not end-of-therapy function, predicted that survivors would have poor executive function of fluency and flexibility at long-term follow up.

Dr. Nathan praised the investigators for their foresight to collect data on the methotrexate area under the curve, number of triple intrathecal therapies (cytarabine, methotrexate, and hydrocortisone), and neurocognitive functioning at the end of chemotherapy. “What’s clear is that chemotherapy alone can lead to neurocognitive late effects,” he said. “But what’s also important is that not all late effects can be predicted by end of therapy assessments.” These late effects appear to evolve over time, so ongoing assessments are needed.

Dr. Turcotte, Dr. Liu, Dr. Levine, and Dr. Nathan each reported no financial disclosures.

NEW ORLEANS — The bionic pancreas, otherwise known as the closed-loop system, can effectively control blood glucose levels and hypoglycemia in adults with type 1 diabetes, according to three different early-stage studies presented at the annual scientific sessions of the American Diabetes Association.

Edward R. Damiano, Ph.D., professor of biomedical engineering at Boston University and co-developer of an iPhone-based bionic pancreas that releases both glucagon and insulin, reported results from the first study of the fully automated device.

Dr. Damiano described this bionic pancreas as a “cobbling together of components” – an iPhone with an app that uses algorithms to control continuous glucose monitor and a couple of pumps that use an unstable form of glucagon that has to be reconstituted every day. Since the study, he and his colleagues have created a company, Beta Bionics, to develop a fully integrated device that replaces the iPhone with a self-contained unit called the iLet that runs on two AA batteries.

©Wavebreakmedia Ltd

The first study of the bionic pancreas was a randomized, cross-over study of 39 adults with type 1 diabetes who used the bionic pancreas for 11 consecutive days and then their own insulin pump for 11 days, or vice versa, while continuing their normal activity.

“What we found with the multi-center study relative to insulin pump therapy, the bionic pancreas is associated with a reduction in both the blood sugar level in the 20 mg/dL mean glucose range as well as the simultaneous reduction in hypoglycemia,” Dr. Damiano said. He added that the bionic pancreas also resulted in less variability in blood glucose levels in individual participants, with a standard deviation of ±10 mg/dL vs. ±30 mg/dL for the insulin pump.

“Our goal is to bring this into clinical trials later this year and start the final pivotal trial in the first half of next year,” Dr. Damiano said, with commercial availability expected by 2018.

Another study of a bionic pancreas investigated automated glucagon-only delivery to reduce the severity and frequency of hypoglycemia. Courtney Balliro of Massachusetts General Hospital, Boston, explained that the double-blind, randomized, placebo-controlled crossover trial involved 22 patients with type 1 diabetes who use an insulin pump or daily insulin injections, but had reduced awareness of hypoglycemia.

The patients wore an experimental closed-loop device to deliver glucagon or a placebo device. “Our study found that using automatic glucagon delivery reduced hypoglycemia by 75% during the day and 91% at night,” the registered nurse reported. The goal is to develop a device that delivers both insulin and glucagon for type 1 diabetics, but a glucagon-only version could be an option for people with type 1 diabetes who are already comfortable with an insulin regimen, either by pump or self-administration, and people with type 2 diabetes or those who have had bariatric surgery.

The third study compared the effectiveness of a bihormonal bionic pancreas – one that delivers both insulin and glucagon – with a system that uses the same insulin algorithm as the bihormonal system to deliver insulin only. Dr. Laya Ekhlaspour of MassGeneral Hospital for Children, Boston, explained the system was configured with a higher glucose target than the 100 mg/dL used in previous bionic pancreas trials to determine if the insulin-only version could both effectively control blood glucose levels and maintain low rates of hypoglycemia.

This random-order, crossover study, involved two insulin-only configurations of the bionic pancreas (at glucose targets of 130 mg/dL and 145 mg/dL), comparing them with three bihormonal configurations (glucose target of 130 mg/dL, 115 mg/dL, and 100 mg/dL) and to usual care (patient-managed, conventional insulin pump therapy) over 3 days. Twenty subjects completed the study.

Raising the blood glucose target to 130 mg/dL increased the mean glucose the bihormonal bionic pancreas achieved (156 mg/dL in the 130-mg/dL configuration vs. 146 mg/dL in the 115-mg/dL target configuration vs. 136 mg/dl in the 100-mg/dL configuration, P less than or equal to .016 for each comparison). But the target glucose of 130 mg/dl yielded no significant difference between the mean glucose achieved in the insulin-only configuration and the bihormonal configuration of the bionic pancreas (161 mg/dL vs.156 mg/dL, P greater than 0.28, respectively), and no difference in hypoglycemia between the two bionic pancreas configurations (0.8% vs. 0.6%, P greater than .28). Likewise, both bionic pancreas configurations at the 130-mg/dl target had similar mean glucose and hypoglycemia vs. the usual care arm.

Dr. Ekhlaspour explained that the goal now is to complete two more arms of the study with a blood glucose target of 110 mg/dL. “We’re hoping we can release the results in the next couple of months, and these results will inform us of what glucose target we can use in a much larger pivotal study with the insulin-only version of the bionic pancreas in 2017,” Dr. Ekhlaspour said.

Vincent Crabtree, Ph.D., director of research business development for the Juvenile Diabetes Research Foundation, said he is encouraged by the studies. “They reinforce everyone’s belief that artificial pancreas/bionic pancreas systems can make a tremendous difference in the lives of people with type 1 diabetes by both reducing the day-to-day unrelenting burden of managing the disease and simultaneously improving the long term outcomes.”

The iLet development team included Steven J. Russell, M.D., Ph.D., assistant professor of medicine at the Diabetes Research Center at Massachusetts General Hospital, Boston. In a video interview at the meeting, Dr. Russell discussed the iLet device and the results of the 39-patient study.

Besides Dr. Damiano’s commercial interest in Beta Bionics, he also disclosed relationships with Dexcom, Eli Lily, Tandem Diabetes Care, NOVA Biomedical, and Sweetspot Diabetes. Dr. Russell disclosed relationships with Abbott Diabetes Care, Beta Bionics, Companion Medical, Dexcom, Eli Lilly, Insulet, International Biomedical, Medtronic MiniMed, Sanofi U.S., and Tandem Diabetes Care. The other study authors had no financial relationships to disclose.

NEW ORLEANS — The bionic pancreas, otherwise known as the closed-loop system, can effectively control blood glucose levels and hypoglycemia in adults with type 1 diabetes, according to three different early-stage studies presented at the annual scientific sessions of the American Diabetes Association.

Edward R. Damiano, Ph.D., professor of biomedical engineering at Boston University and co-developer of an iPhone-based bionic pancreas that releases both glucagon and insulin, reported results from the first study of the fully automated device.

Dr. Damiano described this bionic pancreas as a “cobbling together of components” – an iPhone with an app that uses algorithms to control continuous glucose monitor and a couple of pumps that use an unstable form of glucagon that has to be reconstituted every day. Since the study, he and his colleagues have created a company, Beta Bionics, to develop a fully integrated device that replaces the iPhone with a self-contained unit called the iLet that runs on two AA batteries.

©Wavebreakmedia Ltd

The first study of the bionic pancreas was a randomized, cross-over study of 39 adults with type 1 diabetes who used the bionic pancreas for 11 consecutive days and then their own insulin pump for 11 days, or vice versa, while continuing their normal activity.

“What we found with the multi-center study relative to insulin pump therapy, the bionic pancreas is associated with a reduction in both the blood sugar level in the 20 mg/dL mean glucose range as well as the simultaneous reduction in hypoglycemia,” Dr. Damiano said. He added that the bionic pancreas also resulted in less variability in blood glucose levels in individual participants, with a standard deviation of ±10 mg/dL vs. ±30 mg/dL for the insulin pump.

“Our goal is to bring this into clinical trials later this year and start the final pivotal trial in the first half of next year,” Dr. Damiano said, with commercial availability expected by 2018.

Another study of a bionic pancreas investigated automated glucagon-only delivery to reduce the severity and frequency of hypoglycemia. Courtney Balliro of Massachusetts General Hospital, Boston, explained that the double-blind, randomized, placebo-controlled crossover trial involved 22 patients with type 1 diabetes who use an insulin pump or daily insulin injections, but had reduced awareness of hypoglycemia.

The patients wore an experimental closed-loop device to deliver glucagon or a placebo device. “Our study found that using automatic glucagon delivery reduced hypoglycemia by 75% during the day and 91% at night,” the registered nurse reported. The goal is to develop a device that delivers both insulin and glucagon for type 1 diabetics, but a glucagon-only version could be an option for people with type 1 diabetes who are already comfortable with an insulin regimen, either by pump or self-administration, and people with type 2 diabetes or those who have had bariatric surgery.

The third study compared the effectiveness of a bihormonal bionic pancreas – one that delivers both insulin and glucagon – with a system that uses the same insulin algorithm as the bihormonal system to deliver insulin only. Dr. Laya Ekhlaspour of MassGeneral Hospital for Children, Boston, explained the system was configured with a higher glucose target than the 100 mg/dL used in previous bionic pancreas trials to determine if the insulin-only version could both effectively control blood glucose levels and maintain low rates of hypoglycemia.

This random-order, crossover study, involved two insulin-only configurations of the bionic pancreas (at glucose targets of 130 mg/dL and 145 mg/dL), comparing them with three bihormonal configurations (glucose target of 130 mg/dL, 115 mg/dL, and 100 mg/dL) and to usual care (patient-managed, conventional insulin pump therapy) over 3 days. Twenty subjects completed the study.

Raising the blood glucose target to 130 mg/dL increased the mean glucose the bihormonal bionic pancreas achieved (156 mg/dL in the 130-mg/dL configuration vs. 146 mg/dL in the 115-mg/dL target configuration vs. 136 mg/dl in the 100-mg/dL configuration, P less than or equal to .016 for each comparison). But the target glucose of 130 mg/dl yielded no significant difference between the mean glucose achieved in the insulin-only configuration and the bihormonal configuration of the bionic pancreas (161 mg/dL vs.156 mg/dL, P greater than 0.28, respectively), and no difference in hypoglycemia between the two bionic pancreas configurations (0.8% vs. 0.6%, P greater than .28). Likewise, both bionic pancreas configurations at the 130-mg/dl target had similar mean glucose and hypoglycemia vs. the usual care arm.

Dr. Ekhlaspour explained that the goal now is to complete two more arms of the study with a blood glucose target of 110 mg/dL. “We’re hoping we can release the results in the next couple of months, and these results will inform us of what glucose target we can use in a much larger pivotal study with the insulin-only version of the bionic pancreas in 2017,” Dr. Ekhlaspour said.

Vincent Crabtree, Ph.D., director of research business development for the Juvenile Diabetes Research Foundation, said he is encouraged by the studies. “They reinforce everyone’s belief that artificial pancreas/bionic pancreas systems can make a tremendous difference in the lives of people with type 1 diabetes by both reducing the day-to-day unrelenting burden of managing the disease and simultaneously improving the long term outcomes.”

The iLet development team included Steven J. Russell, M.D., Ph.D., assistant professor of medicine at the Diabetes Research Center at Massachusetts General Hospital, Boston. In a video interview at the meeting, Dr. Russell discussed the iLet device and the results of the 39-patient study.

Besides Dr. Damiano’s commercial interest in Beta Bionics, he also disclosed relationships with Dexcom, Eli Lily, Tandem Diabetes Care, NOVA Biomedical, and Sweetspot Diabetes. Dr. Russell disclosed relationships with Abbott Diabetes Care, Beta Bionics, Companion Medical, Dexcom, Eli Lilly, Insulet, International Biomedical, Medtronic MiniMed, Sanofi U.S., and Tandem Diabetes Care. The other study authors had no financial relationships to disclose.

NEW ORLEANS — The bionic pancreas, otherwise known as the closed-loop system, can effectively control blood glucose levels and hypoglycemia in adults with type 1 diabetes, according to three different early-stage studies presented at the annual scientific sessions of the American Diabetes Association.

Edward R. Damiano, Ph.D., professor of biomedical engineering at Boston University and co-developer of an iPhone-based bionic pancreas that releases both glucagon and insulin, reported results from the first study of the fully automated device.

Dr. Damiano described this bionic pancreas as a “cobbling together of components” – an iPhone with an app that uses algorithms to control continuous glucose monitor and a couple of pumps that use an unstable form of glucagon that has to be reconstituted every day. Since the study, he and his colleagues have created a company, Beta Bionics, to develop a fully integrated device that replaces the iPhone with a self-contained unit called the iLet that runs on two AA batteries.

©Wavebreakmedia Ltd

The first study of the bionic pancreas was a randomized, cross-over study of 39 adults with type 1 diabetes who used the bionic pancreas for 11 consecutive days and then their own insulin pump for 11 days, or vice versa, while continuing their normal activity.

“What we found with the multi-center study relative to insulin pump therapy, the bionic pancreas is associated with a reduction in both the blood sugar level in the 20 mg/dL mean glucose range as well as the simultaneous reduction in hypoglycemia,” Dr. Damiano said. He added that the bionic pancreas also resulted in less variability in blood glucose levels in individual participants, with a standard deviation of ±10 mg/dL vs. ±30 mg/dL for the insulin pump.

“Our goal is to bring this into clinical trials later this year and start the final pivotal trial in the first half of next year,” Dr. Damiano said, with commercial availability expected by 2018.

Another study of a bionic pancreas investigated automated glucagon-only delivery to reduce the severity and frequency of hypoglycemia. Courtney Balliro of Massachusetts General Hospital, Boston, explained that the double-blind, randomized, placebo-controlled crossover trial involved 22 patients with type 1 diabetes who use an insulin pump or daily insulin injections, but had reduced awareness of hypoglycemia.

The patients wore an experimental closed-loop device to deliver glucagon or a placebo device. “Our study found that using automatic glucagon delivery reduced hypoglycemia by 75% during the day and 91% at night,” the registered nurse reported. The goal is to develop a device that delivers both insulin and glucagon for type 1 diabetics, but a glucagon-only version could be an option for people with type 1 diabetes who are already comfortable with an insulin regimen, either by pump or self-administration, and people with type 2 diabetes or those who have had bariatric surgery.

The third study compared the effectiveness of a bihormonal bionic pancreas – one that delivers both insulin and glucagon – with a system that uses the same insulin algorithm as the bihormonal system to deliver insulin only. Dr. Laya Ekhlaspour of MassGeneral Hospital for Children, Boston, explained the system was configured with a higher glucose target than the 100 mg/dL used in previous bionic pancreas trials to determine if the insulin-only version could both effectively control blood glucose levels and maintain low rates of hypoglycemia.

This random-order, crossover study, involved two insulin-only configurations of the bionic pancreas (at glucose targets of 130 mg/dL and 145 mg/dL), comparing them with three bihormonal configurations (glucose target of 130 mg/dL, 115 mg/dL, and 100 mg/dL) and to usual care (patient-managed, conventional insulin pump therapy) over 3 days. Twenty subjects completed the study.

Raising the blood glucose target to 130 mg/dL increased the mean glucose the bihormonal bionic pancreas achieved (156 mg/dL in the 130-mg/dL configuration vs. 146 mg/dL in the 115-mg/dL target configuration vs. 136 mg/dl in the 100-mg/dL configuration, P less than or equal to .016 for each comparison). But the target glucose of 130 mg/dl yielded no significant difference between the mean glucose achieved in the insulin-only configuration and the bihormonal configuration of the bionic pancreas (161 mg/dL vs.156 mg/dL, P greater than 0.28, respectively), and no difference in hypoglycemia between the two bionic pancreas configurations (0.8% vs. 0.6%, P greater than .28). Likewise, both bionic pancreas configurations at the 130-mg/dl target had similar mean glucose and hypoglycemia vs. the usual care arm.

Dr. Ekhlaspour explained that the goal now is to complete two more arms of the study with a blood glucose target of 110 mg/dL. “We’re hoping we can release the results in the next couple of months, and these results will inform us of what glucose target we can use in a much larger pivotal study with the insulin-only version of the bionic pancreas in 2017,” Dr. Ekhlaspour said.

Vincent Crabtree, Ph.D., director of research business development for the Juvenile Diabetes Research Foundation, said he is encouraged by the studies. “They reinforce everyone’s belief that artificial pancreas/bionic pancreas systems can make a tremendous difference in the lives of people with type 1 diabetes by both reducing the day-to-day unrelenting burden of managing the disease and simultaneously improving the long term outcomes.”

The iLet development team included Steven J. Russell, M.D., Ph.D., assistant professor of medicine at the Diabetes Research Center at Massachusetts General Hospital, Boston. In a video interview at the meeting, Dr. Russell discussed the iLet device and the results of the 39-patient study.

Besides Dr. Damiano’s commercial interest in Beta Bionics, he also disclosed relationships with Dexcom, Eli Lily, Tandem Diabetes Care, NOVA Biomedical, and Sweetspot Diabetes. Dr. Russell disclosed relationships with Abbott Diabetes Care, Beta Bionics, Companion Medical, Dexcom, Eli Lilly, Insulet, International Biomedical, Medtronic MiniMed, Sanofi U.S., and Tandem Diabetes Care. The other study authors had no financial relationships to disclose.

Poster session at ASCO 2016
© ASCO/Zach Boyden-Holmes

CHICAGO—Investigators have found an increased risk in cancer incidence for patients with primary immunodeficiency diseases (PIDD), and in particular, a significant increase in lymphoma cases.

Investigators reviewed records of patients registered in the United States Immune Deficiency Network (USIDNET) and found they had a 42% increase in cancer incidence overall compared to the general population in the Surveillance, Epidemiology and End Results (SEER) database.

And lymphoma incidence was 10 times higher among men and 8 times higher among women in the USIDNET registry.

The USIDNET registry collects information, including clinical, laboratory, and outcome data, on patients affected by PIDD. Site-specific cancer incidence rates are included in the registry.

Investigators compared data from the 2 registries based on age and gender. They abstracted data on 3665 patients from the USIDNET Registry from 2003 to 2015 and generated site-specific incidence rates for them. They also generated age adjusted incidence rates using the SEER database for comparison.

The investigators observed a 1.34-fold excess relative risk of cancer (P<0.001) in patients with PIDD compared to the age-adjusted SEER population.

They also discovered that in men, the relative risk increased to 1.8-fold (P<0.001), while in women, the excess relative risk of cancer was not significant.

Men also had a statistically significant increase in skin cancer (4.45-fold excess relative risk, P<0.001) and thyroid cancer (4-fold excess relative risk, P=0.002).

Women had a statistically significant increase in skin (3.19-fold excess relative risk, P<0.001) and stomach cancer (3-fold excess relative risk, P=0.015).

And both men and women had a statistically significant increase in lymphoma, at a significance of P<0.001 for each gender.

“This study found that patients with primary immunodeficiency disorders have a modest increase in overall cancer incidence,” senior author, Brahm Segal, MD, of Roswell Park Cancer Institute in Buffalo, New York, said, “driven by specific primary immunodeficiency disorders predisposing to specific cancers, particularly lymphoma.”

The investigators did not observe an increased risk for the most common solid tumor cancers, including breast, lung, prostate, and colon.

The investigators believe the findings point to a “restricted role of the immune system in protecting from specific cancers and question the role of immunosurveillance in incident risk of common solid tumor cancers.”

They reported their findings at the 2016 ASCO Annual Meeting as abstract 1520.

Poster session at ASCO 2016
© ASCO/Zach Boyden-Holmes

CHICAGO—Investigators have found an increased risk in cancer incidence for patients with primary immunodeficiency diseases (PIDD), and in particular, a significant increase in lymphoma cases.

Investigators reviewed records of patients registered in the United States Immune Deficiency Network (USIDNET) and found they had a 42% increase in cancer incidence overall compared to the general population in the Surveillance, Epidemiology and End Results (SEER) database.

And lymphoma incidence was 10 times higher among men and 8 times higher among women in the USIDNET registry.

The USIDNET registry collects information, including clinical, laboratory, and outcome data, on patients affected by PIDD. Site-specific cancer incidence rates are included in the registry.

Investigators compared data from the 2 registries based on age and gender. They abstracted data on 3665 patients from the USIDNET Registry from 2003 to 2015 and generated site-specific incidence rates for them. They also generated age adjusted incidence rates using the SEER database for comparison.

The investigators observed a 1.34-fold excess relative risk of cancer (P<0.001) in patients with PIDD compared to the age-adjusted SEER population.

They also discovered that in men, the relative risk increased to 1.8-fold (P<0.001), while in women, the excess relative risk of cancer was not significant.

Men also had a statistically significant increase in skin cancer (4.45-fold excess relative risk, P<0.001) and thyroid cancer (4-fold excess relative risk, P=0.002).

Women had a statistically significant increase in skin (3.19-fold excess relative risk, P<0.001) and stomach cancer (3-fold excess relative risk, P=0.015).

And both men and women had a statistically significant increase in lymphoma, at a significance of P<0.001 for each gender.

“This study found that patients with primary immunodeficiency disorders have a modest increase in overall cancer incidence,” senior author, Brahm Segal, MD, of Roswell Park Cancer Institute in Buffalo, New York, said, “driven by specific primary immunodeficiency disorders predisposing to specific cancers, particularly lymphoma.”

The investigators did not observe an increased risk for the most common solid tumor cancers, including breast, lung, prostate, and colon.

The investigators believe the findings point to a “restricted role of the immune system in protecting from specific cancers and question the role of immunosurveillance in incident risk of common solid tumor cancers.”

They reported their findings at the 2016 ASCO Annual Meeting as abstract 1520.

Poster session at ASCO 2016
© ASCO/Zach Boyden-Holmes

CHICAGO—Investigators have found an increased risk in cancer incidence for patients with primary immunodeficiency diseases (PIDD), and in particular, a significant increase in lymphoma cases.

Investigators reviewed records of patients registered in the United States Immune Deficiency Network (USIDNET) and found they had a 42% increase in cancer incidence overall compared to the general population in the Surveillance, Epidemiology and End Results (SEER) database.

And lymphoma incidence was 10 times higher among men and 8 times higher among women in the USIDNET registry.

The USIDNET registry collects information, including clinical, laboratory, and outcome data, on patients affected by PIDD. Site-specific cancer incidence rates are included in the registry.

Investigators compared data from the 2 registries based on age and gender. They abstracted data on 3665 patients from the USIDNET Registry from 2003 to 2015 and generated site-specific incidence rates for them. They also generated age adjusted incidence rates using the SEER database for comparison.

The investigators observed a 1.34-fold excess relative risk of cancer (P<0.001) in patients with PIDD compared to the age-adjusted SEER population.

They also discovered that in men, the relative risk increased to 1.8-fold (P<0.001), while in women, the excess relative risk of cancer was not significant.

Men also had a statistically significant increase in skin cancer (4.45-fold excess relative risk, P<0.001) and thyroid cancer (4-fold excess relative risk, P=0.002).

Women had a statistically significant increase in skin (3.19-fold excess relative risk, P<0.001) and stomach cancer (3-fold excess relative risk, P=0.015).

And both men and women had a statistically significant increase in lymphoma, at a significance of P<0.001 for each gender.

“This study found that patients with primary immunodeficiency disorders have a modest increase in overall cancer incidence,” senior author, Brahm Segal, MD, of Roswell Park Cancer Institute in Buffalo, New York, said, “driven by specific primary immunodeficiency disorders predisposing to specific cancers, particularly lymphoma.”

The investigators did not observe an increased risk for the most common solid tumor cancers, including breast, lung, prostate, and colon.

The investigators believe the findings point to a “restricted role of the immune system in protecting from specific cancers and question the role of immunosurveillance in incident risk of common solid tumor cancers.”

They reported their findings at the 2016 ASCO Annual Meeting as abstract 1520.

LONDON – The option of treating axial spondyloarthritis with an interleukin-17 inhibitor has become an officially recommended option for the first time in a new update to management recommendations for this disease released by a task force assembled jointly by the Assessment of SpondyloArthritis International Society and the European League Against Rheumatism.

The update replaces recommendations last released by the two groups for managing patients with ankylosing spondylitis in 2010 (Ann Rheum Dis. 2011 June;70[6]:896-904), as well as the prior recommendations from the two organizations for using tumor necrosis factor (TNF) inhibitors on these patients (Ann Rheum Dis. 2011 June;70[6]:905-8). The new update also broadens the disease spectrum from ankylosing spondylitis to axial spondyloarthritis (SpA).

Mitchel L. Zoler/Frontline Medical News

The latest recommendations continue to place nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line pharmacotherapy for patients with axial SpA to control pain and stiffness, and continue to place treatment with a biological disease modifying antirheumatic drug (DMARD) – identified in the recommendations as most typically a TNF inhibitor by current practice – as second-line treatment after NSAIDs. The recommendations specify that initiation of a biological DMARD should target patients who have both failed treatment with at least two different NSAIDs over the course of at least 4 weeks of treatment, and who have active disease documented by either of two standard measures of disease activity in patients with axial SpA: either a score of at least 2.1 on the ankylosing spondylitis disease activity score (ASDAS) or a score of at least 4 on the Bath ankylosing spondylitis disease activity index (BASDAI).

Incorporation of the ASDAS as a potential alternative to the BASDAI for assessing disease activity in these patients is another new feature of these recommendations, noted Dr. Désirée van der Heijde, convenor of the update task force, who presented the new recommendations at the European Congress of Rheumatology.

The new recommendations place use of an interleukin (IL)-17 inhibitor as a third-line management option, for patients who fail to adequately respond to a first TNF inhibitor, and they also say that an alternative to starting an IL-17 inhibitor at this stage of management is to instead try treatment with a second type of TNF inhibitor. The IL-17 inhibitor class includes secukinumab (Cosentyx), which received approval from the Food and Drug Administration for treating active ankylosing spondylitis in January 2016, and which also has approval for the same indication from the European Medicines Agency.

The updated recommendations leave unchanged from the prior version advice to use biological DMARDs only after failure of other treatments, as well as advocacy of nondrug therapy with regular exercise, smoking cessation, and physical therapy when appropriate as the very first therapeutic step to take, before even starting a NSAID regimen. For patients with axial SpA who have peripheral arthritis, the recommendations say that clinicians can consider treatment with a local injection of a glucocorticoid, and a treatment course with sulfasalazine. The recommendations do not endorse treatment with a conventional, synthetic DMARD for patients with purely axial disease, and they also recommend against long-term treatment with a systemic corticosteroid. The update calls analgesics contraindicated.

Another new feature of the updated recommendations is endorsement of treating axial SpA patients to a predefined treatment target, although the recommendations left the nature of that target undefined and is something for the treating clinician to discuss and tailor to each patient individually, said Dr. van der Heijde, professor of rheumatology at Leiden University Medical Center in The Netherlands. The update also introduces for the first time the recommendation to consider tapering down treatment with a biological DMARD for patients who achieve remission.

Dr. van der Heijde said that she has been a consultant to 17 drug companies.

[email protected]

On Twitter @mitchelzoler

LONDON – The option of treating axial spondyloarthritis with an interleukin-17 inhibitor has become an officially recommended option for the first time in a new update to management recommendations for this disease released by a task force assembled jointly by the Assessment of SpondyloArthritis International Society and the European League Against Rheumatism.

The update replaces recommendations last released by the two groups for managing patients with ankylosing spondylitis in 2010 (Ann Rheum Dis. 2011 June;70[6]:896-904), as well as the prior recommendations from the two organizations for using tumor necrosis factor (TNF) inhibitors on these patients (Ann Rheum Dis. 2011 June;70[6]:905-8). The new update also broadens the disease spectrum from ankylosing spondylitis to axial spondyloarthritis (SpA).

Mitchel L. Zoler/Frontline Medical News

The latest recommendations continue to place nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line pharmacotherapy for patients with axial SpA to control pain and stiffness, and continue to place treatment with a biological disease modifying antirheumatic drug (DMARD) – identified in the recommendations as most typically a TNF inhibitor by current practice – as second-line treatment after NSAIDs. The recommendations specify that initiation of a biological DMARD should target patients who have both failed treatment with at least two different NSAIDs over the course of at least 4 weeks of treatment, and who have active disease documented by either of two standard measures of disease activity in patients with axial SpA: either a score of at least 2.1 on the ankylosing spondylitis disease activity score (ASDAS) or a score of at least 4 on the Bath ankylosing spondylitis disease activity index (BASDAI).

Incorporation of the ASDAS as a potential alternative to the BASDAI for assessing disease activity in these patients is another new feature of these recommendations, noted Dr. Désirée van der Heijde, convenor of the update task force, who presented the new recommendations at the European Congress of Rheumatology.

The new recommendations place use of an interleukin (IL)-17 inhibitor as a third-line management option, for patients who fail to adequately respond to a first TNF inhibitor, and they also say that an alternative to starting an IL-17 inhibitor at this stage of management is to instead try treatment with a second type of TNF inhibitor. The IL-17 inhibitor class includes secukinumab (Cosentyx), which received approval from the Food and Drug Administration for treating active ankylosing spondylitis in January 2016, and which also has approval for the same indication from the European Medicines Agency.

The updated recommendations leave unchanged from the prior version advice to use biological DMARDs only after failure of other treatments, as well as advocacy of nondrug therapy with regular exercise, smoking cessation, and physical therapy when appropriate as the very first therapeutic step to take, before even starting a NSAID regimen. For patients with axial SpA who have peripheral arthritis, the recommendations say that clinicians can consider treatment with a local injection of a glucocorticoid, and a treatment course with sulfasalazine. The recommendations do not endorse treatment with a conventional, synthetic DMARD for patients with purely axial disease, and they also recommend against long-term treatment with a systemic corticosteroid. The update calls analgesics contraindicated.

Another new feature of the updated recommendations is endorsement of treating axial SpA patients to a predefined treatment target, although the recommendations left the nature of that target undefined and is something for the treating clinician to discuss and tailor to each patient individually, said Dr. van der Heijde, professor of rheumatology at Leiden University Medical Center in The Netherlands. The update also introduces for the first time the recommendation to consider tapering down treatment with a biological DMARD for patients who achieve remission.

Dr. van der Heijde said that she has been a consultant to 17 drug companies.

[email protected]

On Twitter @mitchelzoler

LONDON – The option of treating axial spondyloarthritis with an interleukin-17 inhibitor has become an officially recommended option for the first time in a new update to management recommendations for this disease released by a task force assembled jointly by the Assessment of SpondyloArthritis International Society and the European League Against Rheumatism.

The update replaces recommendations last released by the two groups for managing patients with ankylosing spondylitis in 2010 (Ann Rheum Dis. 2011 June;70[6]:896-904), as well as the prior recommendations from the two organizations for using tumor necrosis factor (TNF) inhibitors on these patients (Ann Rheum Dis. 2011 June;70[6]:905-8). The new update also broadens the disease spectrum from ankylosing spondylitis to axial spondyloarthritis (SpA).

Mitchel L. Zoler/Frontline Medical News

The latest recommendations continue to place nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line pharmacotherapy for patients with axial SpA to control pain and stiffness, and continue to place treatment with a biological disease modifying antirheumatic drug (DMARD) – identified in the recommendations as most typically a TNF inhibitor by current practice – as second-line treatment after NSAIDs. The recommendations specify that initiation of a biological DMARD should target patients who have both failed treatment with at least two different NSAIDs over the course of at least 4 weeks of treatment, and who have active disease documented by either of two standard measures of disease activity in patients with axial SpA: either a score of at least 2.1 on the ankylosing spondylitis disease activity score (ASDAS) or a score of at least 4 on the Bath ankylosing spondylitis disease activity index (BASDAI).

Incorporation of the ASDAS as a potential alternative to the BASDAI for assessing disease activity in these patients is another new feature of these recommendations, noted Dr. Désirée van der Heijde, convenor of the update task force, who presented the new recommendations at the European Congress of Rheumatology.

The new recommendations place use of an interleukin (IL)-17 inhibitor as a third-line management option, for patients who fail to adequately respond to a first TNF inhibitor, and they also say that an alternative to starting an IL-17 inhibitor at this stage of management is to instead try treatment with a second type of TNF inhibitor. The IL-17 inhibitor class includes secukinumab (Cosentyx), which received approval from the Food and Drug Administration for treating active ankylosing spondylitis in January 2016, and which also has approval for the same indication from the European Medicines Agency.

The updated recommendations leave unchanged from the prior version advice to use biological DMARDs only after failure of other treatments, as well as advocacy of nondrug therapy with regular exercise, smoking cessation, and physical therapy when appropriate as the very first therapeutic step to take, before even starting a NSAID regimen. For patients with axial SpA who have peripheral arthritis, the recommendations say that clinicians can consider treatment with a local injection of a glucocorticoid, and a treatment course with sulfasalazine. The recommendations do not endorse treatment with a conventional, synthetic DMARD for patients with purely axial disease, and they also recommend against long-term treatment with a systemic corticosteroid. The update calls analgesics contraindicated.

Another new feature of the updated recommendations is endorsement of treating axial SpA patients to a predefined treatment target, although the recommendations left the nature of that target undefined and is something for the treating clinician to discuss and tailor to each patient individually, said Dr. van der Heijde, professor of rheumatology at Leiden University Medical Center in The Netherlands. The update also introduces for the first time the recommendation to consider tapering down treatment with a biological DMARD for patients who achieve remission.

Dr. van der Heijde said that she has been a consultant to 17 drug companies.

[email protected]

On Twitter @mitchelzoler

NEW ORLEANS – Patients with diabetes and peripheral neuropathy who used a smart watch and specially designed smart insoles equipped with an alert system minimized their reulceration risk, results from a proof-of-concept study demonstrated.

The findings suggest that mobile health “could be an effective method to educate patients to change their harmful activity behavior, could enhance adherence to regularly inspect their feet and seek for care in a timely manner, and ultimately may assist in prevention of recurrence of ulcers,” lead author Bijan Najafi, Ph.D., said in an interview in advance of the annual scientific sessions of the American Diabetes Association.

Dr. Najafi, professor of surgery at Baylor College of Medicine, Houston, said that in 2015, approximately one-third of all diabetes-related costs in the United States were spent on diabetic foot ulcers (DFUs). “Unfortunately, many DFUs end up in amputation, which could devastate patients and their families,” he said. “On the same note, persons within the lowest income brackets are estimated to have 38% higher amputation rate, compared with those in the highest income bracket. All these highlight an important gap in effective management of DFUs, in particular among poor working-class people.”

He also noted that DFU recurrence rates are 30%-40% in the first year, compared with 7.5% annual incidence for patients with peripheral neuropathy and no ulcer history. “The good news is that 75% of recurrent foot ulcers are preventable,” said Dr. Najafi, who is also director of clinical research in Baylor’s division of vascular surgery and endovascular therapy and director of the Interdisciplinary Consortium on Advanced Motion Performance. “An effective method is empowering patients to take care of their own health via regular self-inspection of their feet as well as providing timely and personalized foot care. The big challenge is adherence to prevention and regular foot inspection.”

In a study supported in part by Orpyx Medical Technologies, the investigators used a smart watch and smart insoles to enhance adherence to footwear and effective offloading by providing real-time feedback to 19 patients at high risk of DFUs about a harmful plantar pressure event. The patients wore the insole system for 3 months and were alerted through a smart watch if their plantar pressure exceeded 50 mm Hg over 95% of a moving 15-minute window. A successful response to an alert was recorded when offloading occurred within 20 minutes.

Dr. Najafi reported that by the third month, patients who received a higher number of alerts were more likely to use devices and technique to offload weight from their foot, compared with those who received a lower number of alerts (55% vs. 17%, respectively; P less than .01). In addition, patients whose wear time increased during the study tended to have more alerts, compared with other participants (a mean of .82 vs. .36 alerts per hour; P = .09). The best results occurred when patients received at least one alert every 2 hours. “We found that those who frequently received alerts about harmful plantar pressure events improved their adherence to the prescribed footwear and were more responsive to alerts,” he said. At the same time, those patients who received fewer alerts per day, “started to neglect alerts and adherence to footwear over time, despite having initially good adherence at the first month.”

Going forward, Dr. Najafi said, a key challenge is to continue engaging patients to use such technologies on a daily basis. “This could be addressable by providing frequent and comprehensive alerts which not only address harmful plantar pressure during walking but also any harmful foot-loading conditions, including prolonged harmful foot-loading pressure during standing as well as sitting,” he said.

In a video interview at the meeting, Dr. Najafi discussed the study and the challenges of encouraging treatment adherence.

Orpyx Medical Technologies provided partial funding support for the study. Dr. Najafi reported having no financial disclosures. The other authors of this study are Eyal Ron, Ana Enriquez, Ivan Marin, Jacqueline Lee-Eng, Javad Razjouyan, Ph.D., and Dr. David Armstrong. All subjects were recruited at the University of Arizona, College of Medicine, Tucson.

[email protected]

NEW ORLEANS – Patients with diabetes and peripheral neuropathy who used a smart watch and specially designed smart insoles equipped with an alert system minimized their reulceration risk, results from a proof-of-concept study demonstrated.

The findings suggest that mobile health “could be an effective method to educate patients to change their harmful activity behavior, could enhance adherence to regularly inspect their feet and seek for care in a timely manner, and ultimately may assist in prevention of recurrence of ulcers,” lead author Bijan Najafi, Ph.D., said in an interview in advance of the annual scientific sessions of the American Diabetes Association.

Dr. Najafi, professor of surgery at Baylor College of Medicine, Houston, said that in 2015, approximately one-third of all diabetes-related costs in the United States were spent on diabetic foot ulcers (DFUs). “Unfortunately, many DFUs end up in amputation, which could devastate patients and their families,” he said. “On the same note, persons within the lowest income brackets are estimated to have 38% higher amputation rate, compared with those in the highest income bracket. All these highlight an important gap in effective management of DFUs, in particular among poor working-class people.”

He also noted that DFU recurrence rates are 30%-40% in the first year, compared with 7.5% annual incidence for patients with peripheral neuropathy and no ulcer history. “The good news is that 75% of recurrent foot ulcers are preventable,” said Dr. Najafi, who is also director of clinical research in Baylor’s division of vascular surgery and endovascular therapy and director of the Interdisciplinary Consortium on Advanced Motion Performance. “An effective method is empowering patients to take care of their own health via regular self-inspection of their feet as well as providing timely and personalized foot care. The big challenge is adherence to prevention and regular foot inspection.”

In a study supported in part by Orpyx Medical Technologies, the investigators used a smart watch and smart insoles to enhance adherence to footwear and effective offloading by providing real-time feedback to 19 patients at high risk of DFUs about a harmful plantar pressure event. The patients wore the insole system for 3 months and were alerted through a smart watch if their plantar pressure exceeded 50 mm Hg over 95% of a moving 15-minute window. A successful response to an alert was recorded when offloading occurred within 20 minutes.

Dr. Najafi reported that by the third month, patients who received a higher number of alerts were more likely to use devices and technique to offload weight from their foot, compared with those who received a lower number of alerts (55% vs. 17%, respectively; P less than .01). In addition, patients whose wear time increased during the study tended to have more alerts, compared with other participants (a mean of .82 vs. .36 alerts per hour; P = .09). The best results occurred when patients received at least one alert every 2 hours. “We found that those who frequently received alerts about harmful plantar pressure events improved their adherence to the prescribed footwear and were more responsive to alerts,” he said. At the same time, those patients who received fewer alerts per day, “started to neglect alerts and adherence to footwear over time, despite having initially good adherence at the first month.”

Going forward, Dr. Najafi said, a key challenge is to continue engaging patients to use such technologies on a daily basis. “This could be addressable by providing frequent and comprehensive alerts which not only address harmful plantar pressure during walking but also any harmful foot-loading conditions, including prolonged harmful foot-loading pressure during standing as well as sitting,” he said.

In a video interview at the meeting, Dr. Najafi discussed the study and the challenges of encouraging treatment adherence.

Orpyx Medical Technologies provided partial funding support for the study. Dr. Najafi reported having no financial disclosures. The other authors of this study are Eyal Ron, Ana Enriquez, Ivan Marin, Jacqueline Lee-Eng, Javad Razjouyan, Ph.D., and Dr. David Armstrong. All subjects were recruited at the University of Arizona, College of Medicine, Tucson.

[email protected]

NEW ORLEANS – Patients with diabetes and peripheral neuropathy who used a smart watch and specially designed smart insoles equipped with an alert system minimized their reulceration risk, results from a proof-of-concept study demonstrated.

The findings suggest that mobile health “could be an effective method to educate patients to change their harmful activity behavior, could enhance adherence to regularly inspect their feet and seek for care in a timely manner, and ultimately may assist in prevention of recurrence of ulcers,” lead author Bijan Najafi, Ph.D., said in an interview in advance of the annual scientific sessions of the American Diabetes Association.

Dr. Najafi, professor of surgery at Baylor College of Medicine, Houston, said that in 2015, approximately one-third of all diabetes-related costs in the United States were spent on diabetic foot ulcers (DFUs). “Unfortunately, many DFUs end up in amputation, which could devastate patients and their families,” he said. “On the same note, persons within the lowest income brackets are estimated to have 38% higher amputation rate, compared with those in the highest income bracket. All these highlight an important gap in effective management of DFUs, in particular among poor working-class people.”

He also noted that DFU recurrence rates are 30%-40% in the first year, compared with 7.5% annual incidence for patients with peripheral neuropathy and no ulcer history. “The good news is that 75% of recurrent foot ulcers are preventable,” said Dr. Najafi, who is also director of clinical research in Baylor’s division of vascular surgery and endovascular therapy and director of the Interdisciplinary Consortium on Advanced Motion Performance. “An effective method is empowering patients to take care of their own health via regular self-inspection of their feet as well as providing timely and personalized foot care. The big challenge is adherence to prevention and regular foot inspection.”

In a study supported in part by Orpyx Medical Technologies, the investigators used a smart watch and smart insoles to enhance adherence to footwear and effective offloading by providing real-time feedback to 19 patients at high risk of DFUs about a harmful plantar pressure event. The patients wore the insole system for 3 months and were alerted through a smart watch if their plantar pressure exceeded 50 mm Hg over 95% of a moving 15-minute window. A successful response to an alert was recorded when offloading occurred within 20 minutes.

Dr. Najafi reported that by the third month, patients who received a higher number of alerts were more likely to use devices and technique to offload weight from their foot, compared with those who received a lower number of alerts (55% vs. 17%, respectively; P less than .01). In addition, patients whose wear time increased during the study tended to have more alerts, compared with other participants (a mean of .82 vs. .36 alerts per hour; P = .09). The best results occurred when patients received at least one alert every 2 hours. “We found that those who frequently received alerts about harmful plantar pressure events improved their adherence to the prescribed footwear and were more responsive to alerts,” he said. At the same time, those patients who received fewer alerts per day, “started to neglect alerts and adherence to footwear over time, despite having initially good adherence at the first month.”

Going forward, Dr. Najafi said, a key challenge is to continue engaging patients to use such technologies on a daily basis. “This could be addressable by providing frequent and comprehensive alerts which not only address harmful plantar pressure during walking but also any harmful foot-loading conditions, including prolonged harmful foot-loading pressure during standing as well as sitting,” he said.

In a video interview at the meeting, Dr. Najafi discussed the study and the challenges of encouraging treatment adherence.

Orpyx Medical Technologies provided partial funding support for the study. Dr. Najafi reported having no financial disclosures. The other authors of this study are Eyal Ron, Ana Enriquez, Ivan Marin, Jacqueline Lee-Eng, Javad Razjouyan, Ph.D., and Dr. David Armstrong. All subjects were recruited at the University of Arizona, College of Medicine, Tucson.

[email protected]