User login
Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Worsening osteoporosis care for RA patients shows need for action
Osteoporosis care in patients with rheumatoid arthritis is suboptimal, and the relative risk of the application of appropriate osteoporosis care in both RA and osteoarthritis patients has been declining steadily over the past decade, according to findings from a large, prospective, observational study.
The study included 11,669 RA patients and 2,829 OA patients in the National Data Bank for Rheumatic Diseases who were followed from 2003 through 2014 and showed that about half of the RA patients in whom osteoporosis treatment was indicated never received an osteoporosis medication. Further, the decline in the application of appropriate osteoporosis care was apparent even after the release of the 2010 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, according to the findings, which have been accepted for publication in Arthritis Care & Research (doi: 10.1002/acr.23331).
A more recent study in the general population showed that, regardless of glucocorticoid (GC) use, there was a significant decrease in the use of oral bisphosphonates from 1996 to 2012, noted Dr. Ozen of the University of Nebraska, Omaha, and Marmara University, Istanbul, Turkey.
“The evidence from all these studies suggests that, despite a slight improvement in GIOP care, with a decline in overall OP care in the early 2000s, the OP care gap has always been suboptimal and declined over the last decade significantly,” she said, adding that this is “especially more worrisome in glucocorticoid-receiving RA patients,” in whom bone loss and fracture risk are dramatically increased.
“Additionally, considering that rheumatologists do better regarding comorbidity follow-up and management than other specialists who follow patients with rheumatic diseases, the gap for osteoporosis care might be even higher than we reported,” she said.
Indeed, among physicians caring for patients with osteoporosis, there is concern that “we’re on the precipice of further increase in fracture burden,” according to Kenneth Saag, MD, a rheumatologist and professor at the University of Alabama at Birmingham.
The conclusions of the study by Dr. Ozen and her colleagues are disturbing, but “not tremendously surprising,” said Dr. Saag, who also is president of the National Osteoporosis Foundation.
The findings are consistent with those from previous studies, he explained.
For example, Daniel H. Solomon, MD, and his associates showed that only 23% of 623 RA patients, including 236 patients who were taking glucocorticoids at an index visit in 1999, underwent bone densitometry, and only 42% were prescribed a medication (other than calcium and/or vitamin D), that reduces bone loss (Arthritis Rheum. 2002;46:3136-42). They also showed that, in 2004, despite a slight improvement vs. prior years, only 48% of 193 RA patients included in a chart review had received a bone mineral density test or medication for osteoporosis, and 64% of those taking more than 5 mg of prednisone for more than 3 months were receiving osteoporosis management (Arthritis Care Res. 2006;55:873-7).
In the current study, Dr. Ozen and her colleagues looked at both RA and OA patients and found that overall, osteoporosis treatment or screening was reported in 67.4% of study subjects over a mean of 5.5 years follow-up. Of those eligible for osteoporosis treatment based on the 2010 ACR guidelines, including 48.4% of RA patients and 17.6% of OA patients, 55% reported osteoporosis medication use. Despite their increased risk of osteoporosis, particularly in the setting of glucocorticoid use, RA patients were not more likely than OA patients to undergo screening or receive treatment (hazard ratio, 1.04).
“This suboptimal and decreasing trend for osteoporosis treatment and screening in RA patients is important as the prevalence of osteoporosis leading to fractures in RA, regardless of GC use, is still high, despite aggressive management strategies and the use of [biologic disease-modifying antirheumatic agents],” they wrote.
Factors contributing to the decline
The reasons for the decline after 2008 are not fully known, but data suggest that both patient and clinician factors play a role.
Lack of knowledge, unwillingness to take additional drugs, and cost are among patient factors that may interfere with screening and treatment, and lack of experience and time, and a focus more on disease activity and other comorbid conditions may be among clinician factors, they said.
Other factors that may have affected patient and clinician willingness to pursue care include 2007 cuts in Medicare reimbursement for dual-energy x-ray absorptiometry (DXA), a 2006 warning regarding jaw osteonecrosis with bisphosphonate use, and 2007 and 2010 publications about atrial fibrillation and atypical femoral fractures associated with long-term bisphosphonate treatment, they noted.
Dr. Saag agreed that it is difficult to pinpoint exact reasons for the decline, but said the DXA reimbursement cuts have had a significant effect.
“Declining reimbursement is likely one of the major factors, if not the major factor in the decline in testing that has been observed nationally,” he said, explaining that reimbursement was below the break-even point for many physicians in freestanding medical practices, and that slight adjustments have applied only to facilities located in hospitals. As a result, the availability of DXA screening has declined.
The National Osteoporosis Foundation and other organizations such as the International Society for Clinical Densitometry are lobbying for changes, as there is a very strong link between testing and treatment.
“If we can’t get more people tested, we’re unlikely to get more people treated,” Dr. Saag said.
The availability of new agents for the treatment of osteoporosis could also lead to improvements in screening and care, he added.
In July, Amgen submitted to the Food and Drug Administration a supplemental new Biologics License Application for Prolia (denosumab) for the treatment of patients with GIOP. The application is based on a phase 3 study evaluating the safety and efficacy of Prolia, compared with risedronate, in patients receiving glucocorticoid treatment. Denosumab was also shown in a phase 3 study presented at the 2016 ACR meeting to result in greater improvement in bone mineral density vs. bisphosphonates across multiple sites, said Dr. Saag, an investigator for the trial.
“So we’re pleased about that finding, and we’re hopeful that eventually denosumab may become another treatment option,” he said, adding that having more choices leads to more personalized care for patients.
“We hope that, if it does receive approval and is utilized, that it may partially help address the gap in treatment that has been identified,” he said, adding that abaloparatide (Tymlos), which is approved for use in postmenopausal women with osteoporosis and high fracture risk, and romosozumab, currently in late-phase development, could also eventually help bridge the gap.
Recent guideline update
There is also optimism that a recent update to the 2010 guideline, published in August in Arthritis Care & Research, will help address the problem (Arthritis Care Res. 2017;69:1095-1110).
“We hope that one the most important impacts of the new 2017 ACR GIOP guideline will be increasing the awareness of GIOP care,” Dr. Ozen said, noting that changes in the new guideline will also be helpful for guiding management of certain patients not addressed in the 2010 guideline, including adults under age 40 years and children.
The new guideline also incorporates FRAX hip fracture scores into the risk-assessment recommendations .
“Lastly, the addition of other oral bisphosphonates and denosumab to the guideline has broadened the potential therapeutic options for physicians and patients,” she said.
Efforts by the ACR to make these guidelines widely known among clinicians could also help promote improved screening and treatment, said Dr. Buckley, a professor of internal medicine and pediatrics at Yale University, New Haven, Conn.
And that awareness is what is needed most, Dr. Ozen said.
“What we need in osteoporosis care of RA or GIOP patients is more awareness and education about risk-benefit ratios of antiosteoporotic medications instead of focusing on the medication type. We hope that our paper showing the worsening osteoporosis care and the new 2017 ACR GIOP guideline provide more awareness and guidance for the physicians managing these patients,” she said, adding that overcoming obstacles in osteoporosis care requires identification and attention to all potential causes for the suboptimal management of osteoporosis from both patients’ and physicians’ perspectives.
“With the improvement in management strategies of rheumatic diseases ... we anticipate improvement in life expectancy and cardiovascular outcomes in RA and inflammatory rheumatic diseases. In this regard, with aging and decreased but ongoing clinical or subclinical chronic inflammation, it is highly likely that we might be dealing with much older patients with higher osteoporosis and fracture risks. Considering the significant contribution of fractures on cost, disability, morbidity, and mortality of these diseases, rheumatologists and other specialists should work together more vigilantly to overcome the obstacles and improve osteoporosis care,” she said.
Dr. Ozen and Dr. Buckley reported having no conflicts of interest. Dr. Saag is an investigator and consultant for Amgen, Merck, and Radius Health, and is a consultant for Lilly.
Osteoporosis care in patients with rheumatoid arthritis is suboptimal, and the relative risk of the application of appropriate osteoporosis care in both RA and osteoarthritis patients has been declining steadily over the past decade, according to findings from a large, prospective, observational study.
The study included 11,669 RA patients and 2,829 OA patients in the National Data Bank for Rheumatic Diseases who were followed from 2003 through 2014 and showed that about half of the RA patients in whom osteoporosis treatment was indicated never received an osteoporosis medication. Further, the decline in the application of appropriate osteoporosis care was apparent even after the release of the 2010 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, according to the findings, which have been accepted for publication in Arthritis Care & Research (doi: 10.1002/acr.23331).
A more recent study in the general population showed that, regardless of glucocorticoid (GC) use, there was a significant decrease in the use of oral bisphosphonates from 1996 to 2012, noted Dr. Ozen of the University of Nebraska, Omaha, and Marmara University, Istanbul, Turkey.
“The evidence from all these studies suggests that, despite a slight improvement in GIOP care, with a decline in overall OP care in the early 2000s, the OP care gap has always been suboptimal and declined over the last decade significantly,” she said, adding that this is “especially more worrisome in glucocorticoid-receiving RA patients,” in whom bone loss and fracture risk are dramatically increased.
“Additionally, considering that rheumatologists do better regarding comorbidity follow-up and management than other specialists who follow patients with rheumatic diseases, the gap for osteoporosis care might be even higher than we reported,” she said.
Indeed, among physicians caring for patients with osteoporosis, there is concern that “we’re on the precipice of further increase in fracture burden,” according to Kenneth Saag, MD, a rheumatologist and professor at the University of Alabama at Birmingham.
The conclusions of the study by Dr. Ozen and her colleagues are disturbing, but “not tremendously surprising,” said Dr. Saag, who also is president of the National Osteoporosis Foundation.
The findings are consistent with those from previous studies, he explained.
For example, Daniel H. Solomon, MD, and his associates showed that only 23% of 623 RA patients, including 236 patients who were taking glucocorticoids at an index visit in 1999, underwent bone densitometry, and only 42% were prescribed a medication (other than calcium and/or vitamin D), that reduces bone loss (Arthritis Rheum. 2002;46:3136-42). They also showed that, in 2004, despite a slight improvement vs. prior years, only 48% of 193 RA patients included in a chart review had received a bone mineral density test or medication for osteoporosis, and 64% of those taking more than 5 mg of prednisone for more than 3 months were receiving osteoporosis management (Arthritis Care Res. 2006;55:873-7).
In the current study, Dr. Ozen and her colleagues looked at both RA and OA patients and found that overall, osteoporosis treatment or screening was reported in 67.4% of study subjects over a mean of 5.5 years follow-up. Of those eligible for osteoporosis treatment based on the 2010 ACR guidelines, including 48.4% of RA patients and 17.6% of OA patients, 55% reported osteoporosis medication use. Despite their increased risk of osteoporosis, particularly in the setting of glucocorticoid use, RA patients were not more likely than OA patients to undergo screening or receive treatment (hazard ratio, 1.04).
“This suboptimal and decreasing trend for osteoporosis treatment and screening in RA patients is important as the prevalence of osteoporosis leading to fractures in RA, regardless of GC use, is still high, despite aggressive management strategies and the use of [biologic disease-modifying antirheumatic agents],” they wrote.
Factors contributing to the decline
The reasons for the decline after 2008 are not fully known, but data suggest that both patient and clinician factors play a role.
Lack of knowledge, unwillingness to take additional drugs, and cost are among patient factors that may interfere with screening and treatment, and lack of experience and time, and a focus more on disease activity and other comorbid conditions may be among clinician factors, they said.
Other factors that may have affected patient and clinician willingness to pursue care include 2007 cuts in Medicare reimbursement for dual-energy x-ray absorptiometry (DXA), a 2006 warning regarding jaw osteonecrosis with bisphosphonate use, and 2007 and 2010 publications about atrial fibrillation and atypical femoral fractures associated with long-term bisphosphonate treatment, they noted.
Dr. Saag agreed that it is difficult to pinpoint exact reasons for the decline, but said the DXA reimbursement cuts have had a significant effect.
“Declining reimbursement is likely one of the major factors, if not the major factor in the decline in testing that has been observed nationally,” he said, explaining that reimbursement was below the break-even point for many physicians in freestanding medical practices, and that slight adjustments have applied only to facilities located in hospitals. As a result, the availability of DXA screening has declined.
The National Osteoporosis Foundation and other organizations such as the International Society for Clinical Densitometry are lobbying for changes, as there is a very strong link between testing and treatment.
“If we can’t get more people tested, we’re unlikely to get more people treated,” Dr. Saag said.
The availability of new agents for the treatment of osteoporosis could also lead to improvements in screening and care, he added.
In July, Amgen submitted to the Food and Drug Administration a supplemental new Biologics License Application for Prolia (denosumab) for the treatment of patients with GIOP. The application is based on a phase 3 study evaluating the safety and efficacy of Prolia, compared with risedronate, in patients receiving glucocorticoid treatment. Denosumab was also shown in a phase 3 study presented at the 2016 ACR meeting to result in greater improvement in bone mineral density vs. bisphosphonates across multiple sites, said Dr. Saag, an investigator for the trial.
“So we’re pleased about that finding, and we’re hopeful that eventually denosumab may become another treatment option,” he said, adding that having more choices leads to more personalized care for patients.
“We hope that, if it does receive approval and is utilized, that it may partially help address the gap in treatment that has been identified,” he said, adding that abaloparatide (Tymlos), which is approved for use in postmenopausal women with osteoporosis and high fracture risk, and romosozumab, currently in late-phase development, could also eventually help bridge the gap.
Recent guideline update
There is also optimism that a recent update to the 2010 guideline, published in August in Arthritis Care & Research, will help address the problem (Arthritis Care Res. 2017;69:1095-1110).
“We hope that one the most important impacts of the new 2017 ACR GIOP guideline will be increasing the awareness of GIOP care,” Dr. Ozen said, noting that changes in the new guideline will also be helpful for guiding management of certain patients not addressed in the 2010 guideline, including adults under age 40 years and children.
The new guideline also incorporates FRAX hip fracture scores into the risk-assessment recommendations .
“Lastly, the addition of other oral bisphosphonates and denosumab to the guideline has broadened the potential therapeutic options for physicians and patients,” she said.
Efforts by the ACR to make these guidelines widely known among clinicians could also help promote improved screening and treatment, said Dr. Buckley, a professor of internal medicine and pediatrics at Yale University, New Haven, Conn.
And that awareness is what is needed most, Dr. Ozen said.
“What we need in osteoporosis care of RA or GIOP patients is more awareness and education about risk-benefit ratios of antiosteoporotic medications instead of focusing on the medication type. We hope that our paper showing the worsening osteoporosis care and the new 2017 ACR GIOP guideline provide more awareness and guidance for the physicians managing these patients,” she said, adding that overcoming obstacles in osteoporosis care requires identification and attention to all potential causes for the suboptimal management of osteoporosis from both patients’ and physicians’ perspectives.
“With the improvement in management strategies of rheumatic diseases ... we anticipate improvement in life expectancy and cardiovascular outcomes in RA and inflammatory rheumatic diseases. In this regard, with aging and decreased but ongoing clinical or subclinical chronic inflammation, it is highly likely that we might be dealing with much older patients with higher osteoporosis and fracture risks. Considering the significant contribution of fractures on cost, disability, morbidity, and mortality of these diseases, rheumatologists and other specialists should work together more vigilantly to overcome the obstacles and improve osteoporosis care,” she said.
Dr. Ozen and Dr. Buckley reported having no conflicts of interest. Dr. Saag is an investigator and consultant for Amgen, Merck, and Radius Health, and is a consultant for Lilly.
Osteoporosis care in patients with rheumatoid arthritis is suboptimal, and the relative risk of the application of appropriate osteoporosis care in both RA and osteoarthritis patients has been declining steadily over the past decade, according to findings from a large, prospective, observational study.
The study included 11,669 RA patients and 2,829 OA patients in the National Data Bank for Rheumatic Diseases who were followed from 2003 through 2014 and showed that about half of the RA patients in whom osteoporosis treatment was indicated never received an osteoporosis medication. Further, the decline in the application of appropriate osteoporosis care was apparent even after the release of the 2010 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, according to the findings, which have been accepted for publication in Arthritis Care & Research (doi: 10.1002/acr.23331).
A more recent study in the general population showed that, regardless of glucocorticoid (GC) use, there was a significant decrease in the use of oral bisphosphonates from 1996 to 2012, noted Dr. Ozen of the University of Nebraska, Omaha, and Marmara University, Istanbul, Turkey.
“The evidence from all these studies suggests that, despite a slight improvement in GIOP care, with a decline in overall OP care in the early 2000s, the OP care gap has always been suboptimal and declined over the last decade significantly,” she said, adding that this is “especially more worrisome in glucocorticoid-receiving RA patients,” in whom bone loss and fracture risk are dramatically increased.
“Additionally, considering that rheumatologists do better regarding comorbidity follow-up and management than other specialists who follow patients with rheumatic diseases, the gap for osteoporosis care might be even higher than we reported,” she said.
Indeed, among physicians caring for patients with osteoporosis, there is concern that “we’re on the precipice of further increase in fracture burden,” according to Kenneth Saag, MD, a rheumatologist and professor at the University of Alabama at Birmingham.
The conclusions of the study by Dr. Ozen and her colleagues are disturbing, but “not tremendously surprising,” said Dr. Saag, who also is president of the National Osteoporosis Foundation.
The findings are consistent with those from previous studies, he explained.
For example, Daniel H. Solomon, MD, and his associates showed that only 23% of 623 RA patients, including 236 patients who were taking glucocorticoids at an index visit in 1999, underwent bone densitometry, and only 42% were prescribed a medication (other than calcium and/or vitamin D), that reduces bone loss (Arthritis Rheum. 2002;46:3136-42). They also showed that, in 2004, despite a slight improvement vs. prior years, only 48% of 193 RA patients included in a chart review had received a bone mineral density test or medication for osteoporosis, and 64% of those taking more than 5 mg of prednisone for more than 3 months were receiving osteoporosis management (Arthritis Care Res. 2006;55:873-7).
In the current study, Dr. Ozen and her colleagues looked at both RA and OA patients and found that overall, osteoporosis treatment or screening was reported in 67.4% of study subjects over a mean of 5.5 years follow-up. Of those eligible for osteoporosis treatment based on the 2010 ACR guidelines, including 48.4% of RA patients and 17.6% of OA patients, 55% reported osteoporosis medication use. Despite their increased risk of osteoporosis, particularly in the setting of glucocorticoid use, RA patients were not more likely than OA patients to undergo screening or receive treatment (hazard ratio, 1.04).
“This suboptimal and decreasing trend for osteoporosis treatment and screening in RA patients is important as the prevalence of osteoporosis leading to fractures in RA, regardless of GC use, is still high, despite aggressive management strategies and the use of [biologic disease-modifying antirheumatic agents],” they wrote.
Factors contributing to the decline
The reasons for the decline after 2008 are not fully known, but data suggest that both patient and clinician factors play a role.
Lack of knowledge, unwillingness to take additional drugs, and cost are among patient factors that may interfere with screening and treatment, and lack of experience and time, and a focus more on disease activity and other comorbid conditions may be among clinician factors, they said.
Other factors that may have affected patient and clinician willingness to pursue care include 2007 cuts in Medicare reimbursement for dual-energy x-ray absorptiometry (DXA), a 2006 warning regarding jaw osteonecrosis with bisphosphonate use, and 2007 and 2010 publications about atrial fibrillation and atypical femoral fractures associated with long-term bisphosphonate treatment, they noted.
Dr. Saag agreed that it is difficult to pinpoint exact reasons for the decline, but said the DXA reimbursement cuts have had a significant effect.
“Declining reimbursement is likely one of the major factors, if not the major factor in the decline in testing that has been observed nationally,” he said, explaining that reimbursement was below the break-even point for many physicians in freestanding medical practices, and that slight adjustments have applied only to facilities located in hospitals. As a result, the availability of DXA screening has declined.
The National Osteoporosis Foundation and other organizations such as the International Society for Clinical Densitometry are lobbying for changes, as there is a very strong link between testing and treatment.
“If we can’t get more people tested, we’re unlikely to get more people treated,” Dr. Saag said.
The availability of new agents for the treatment of osteoporosis could also lead to improvements in screening and care, he added.
In July, Amgen submitted to the Food and Drug Administration a supplemental new Biologics License Application for Prolia (denosumab) for the treatment of patients with GIOP. The application is based on a phase 3 study evaluating the safety and efficacy of Prolia, compared with risedronate, in patients receiving glucocorticoid treatment. Denosumab was also shown in a phase 3 study presented at the 2016 ACR meeting to result in greater improvement in bone mineral density vs. bisphosphonates across multiple sites, said Dr. Saag, an investigator for the trial.
“So we’re pleased about that finding, and we’re hopeful that eventually denosumab may become another treatment option,” he said, adding that having more choices leads to more personalized care for patients.
“We hope that, if it does receive approval and is utilized, that it may partially help address the gap in treatment that has been identified,” he said, adding that abaloparatide (Tymlos), which is approved for use in postmenopausal women with osteoporosis and high fracture risk, and romosozumab, currently in late-phase development, could also eventually help bridge the gap.
Recent guideline update
There is also optimism that a recent update to the 2010 guideline, published in August in Arthritis Care & Research, will help address the problem (Arthritis Care Res. 2017;69:1095-1110).
“We hope that one the most important impacts of the new 2017 ACR GIOP guideline will be increasing the awareness of GIOP care,” Dr. Ozen said, noting that changes in the new guideline will also be helpful for guiding management of certain patients not addressed in the 2010 guideline, including adults under age 40 years and children.
The new guideline also incorporates FRAX hip fracture scores into the risk-assessment recommendations .
“Lastly, the addition of other oral bisphosphonates and denosumab to the guideline has broadened the potential therapeutic options for physicians and patients,” she said.
Efforts by the ACR to make these guidelines widely known among clinicians could also help promote improved screening and treatment, said Dr. Buckley, a professor of internal medicine and pediatrics at Yale University, New Haven, Conn.
And that awareness is what is needed most, Dr. Ozen said.
“What we need in osteoporosis care of RA or GIOP patients is more awareness and education about risk-benefit ratios of antiosteoporotic medications instead of focusing on the medication type. We hope that our paper showing the worsening osteoporosis care and the new 2017 ACR GIOP guideline provide more awareness and guidance for the physicians managing these patients,” she said, adding that overcoming obstacles in osteoporosis care requires identification and attention to all potential causes for the suboptimal management of osteoporosis from both patients’ and physicians’ perspectives.
“With the improvement in management strategies of rheumatic diseases ... we anticipate improvement in life expectancy and cardiovascular outcomes in RA and inflammatory rheumatic diseases. In this regard, with aging and decreased but ongoing clinical or subclinical chronic inflammation, it is highly likely that we might be dealing with much older patients with higher osteoporosis and fracture risks. Considering the significant contribution of fractures on cost, disability, morbidity, and mortality of these diseases, rheumatologists and other specialists should work together more vigilantly to overcome the obstacles and improve osteoporosis care,” she said.
Dr. Ozen and Dr. Buckley reported having no conflicts of interest. Dr. Saag is an investigator and consultant for Amgen, Merck, and Radius Health, and is a consultant for Lilly.
FROM ARTHRITIS CARE & RESEARCH
New AML approvals changing the treatment landscape
With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.
Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.
“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.
In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.
Vyxeos
The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.
In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).
“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.
Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.
The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”
“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”
The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.
Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m2), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.
Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.
The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.
“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.
“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.
For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.
The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”
Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.
Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”
Oral targeted therapies
Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.
In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.
Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.
“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.
This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”
Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.
The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.
“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.
Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).
The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.
Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.
Targeted therapies in development
Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.
Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.
For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.
“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”
An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.
Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.
“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.
Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.
“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.
“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”
Future direction and outcomes
So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?
Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.
“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”
Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.
With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.
Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.
“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.
In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.
Vyxeos
The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.
In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).
“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.
Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.
The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”
“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”
The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.
Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m2), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.
Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.
The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.
“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.
“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.
For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.
The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”
Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.
Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”
Oral targeted therapies
Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.
In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.
Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.
“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.
This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”
Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.
The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.
“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.
Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).
The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.
Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.
Targeted therapies in development
Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.
Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.
For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.
“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”
An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.
Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.
“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.
Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.
“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.
“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”
Future direction and outcomes
So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?
Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.
“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”
Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.
With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.
Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.
“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.
In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.
Vyxeos
The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.
In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).
“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.
Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.
The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”
“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”
The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.
Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m2), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.
Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.
The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.
“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.
“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.
For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.
The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”
Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.
Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”
Oral targeted therapies
Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.
In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.
Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.
“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.
This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”
Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.
The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.
“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.
Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).
The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.
Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.
Targeted therapies in development
Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.
Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.
For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.
“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”
An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.
Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.
“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.
Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.
“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.
“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”
Future direction and outcomes
So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?
Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.
“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”
Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.
New recommendations tout biosimilars for rheumatologic diseases
The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.
“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.
The task force, convened in 2016 to address the matter at an international level, included 25 experts from Europe, Japan, and the United States, including 17 rheumatologists, a rheumatologist/regulator, a dermatologist, a gastroenterologist, 2 pharmacologists, 2 patients, and a research fellow. The task force identified five overarching principles and made eight specific recommendations, based on expert opinion and an extensive literature review that yielded 29 relevant full-text papers and 20 relevant abstracts from the 2015 and 2016 American College of Rheumatology and European League Against Rheumatism annual meetings (Ann Rheum Dis. 2017 Sep 2. doi: 10.1136/annrheumdis-2017-211937).
“This statement was intended both to guide clinicians and to serve as a framework for future educational efforts,” they wrote.
The experts based all five overarching principles for the use of biosimilars on level 5, grade D evidence, indicating that they were derived mainly from expert opinion. They determined that:
- Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
- The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
- A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
- Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
- Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.
These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:
1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).
2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).
3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).
4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).
5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).
6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).
7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).
8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).
Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.
“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.
The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.
The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.
“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.
The task force, convened in 2016 to address the matter at an international level, included 25 experts from Europe, Japan, and the United States, including 17 rheumatologists, a rheumatologist/regulator, a dermatologist, a gastroenterologist, 2 pharmacologists, 2 patients, and a research fellow. The task force identified five overarching principles and made eight specific recommendations, based on expert opinion and an extensive literature review that yielded 29 relevant full-text papers and 20 relevant abstracts from the 2015 and 2016 American College of Rheumatology and European League Against Rheumatism annual meetings (Ann Rheum Dis. 2017 Sep 2. doi: 10.1136/annrheumdis-2017-211937).
“This statement was intended both to guide clinicians and to serve as a framework for future educational efforts,” they wrote.
The experts based all five overarching principles for the use of biosimilars on level 5, grade D evidence, indicating that they were derived mainly from expert opinion. They determined that:
- Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
- The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
- A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
- Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
- Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.
These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:
1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).
2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).
3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).
4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).
5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).
6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).
7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).
8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).
Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.
“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.
The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.
The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.
“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.
The task force, convened in 2016 to address the matter at an international level, included 25 experts from Europe, Japan, and the United States, including 17 rheumatologists, a rheumatologist/regulator, a dermatologist, a gastroenterologist, 2 pharmacologists, 2 patients, and a research fellow. The task force identified five overarching principles and made eight specific recommendations, based on expert opinion and an extensive literature review that yielded 29 relevant full-text papers and 20 relevant abstracts from the 2015 and 2016 American College of Rheumatology and European League Against Rheumatism annual meetings (Ann Rheum Dis. 2017 Sep 2. doi: 10.1136/annrheumdis-2017-211937).
“This statement was intended both to guide clinicians and to serve as a framework for future educational efforts,” they wrote.
The experts based all five overarching principles for the use of biosimilars on level 5, grade D evidence, indicating that they were derived mainly from expert opinion. They determined that:
- Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
- The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
- A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
- Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
- Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.
These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:
1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).
2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).
3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).
4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).
5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).
6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).
7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).
8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).
Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.
“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.
The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.
FROM ANNALS OF THE RHEUMATIC DISEASES
Vaccinate and consider tofacitinib monotherapy to prevent herpes zoster in RA
The results of two studies of tofacitinib treatment for rheumatoid arthritis offer evidence to support the use of the drug without concomitant conventional synthetic disease-modifying antirheumatic drugs in order to reduce the risk of risk of herpes zoster infection and the safety of starting the drug 2-3 weeks after administering live zoster vaccine.
The risk of herpes zoster infection was elevated among rheumatoid arthritis (RA) patients receiving tofacitinib (Xeljanz) with glucocorticoids, compared with those receiving tofacitinib monotherapy, according to an analysis of data from 19 phase 2, phase 3, and long-term extension studies of tofacitinib.
“Further, physicians should continue to consider shingles vaccination prior to starting tofacitinib or biologic therapy,” they wrote.
Dr. Winthrop is the first author of a separate phase 2 study that also appears in Arthritis & Rheumatology, which suggests that live zoster vaccine (LZV) is safe in RA patients who start tofacitinib 2-3 weeks after vaccination. The study also showed that varicella-zoster virus (VZV)-specific humoral and cell-mediated immune responses to LZV are similar in tofacitinib- and placebo-treated patients.
“Our study provides the first data with this vaccine in the RA setting and suggests that these patients, even while using nonbiologic DMARDs at the time of vaccination, are capable of mounting adequate immune responses to this vaccine. Further, our data suggest that the use of tofacitinib following VZV vaccination in the RA setting did not impact negatively the vaccine immunogenicity or the time course of the immune response to the vaccine,” he and his colleagues wrote (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40187).
Increased herpes zoster risk in combination therapy
In the first study, herpes zoster (HZ) was reported in 636 of 6,192 patients over a median follow-up of 3 years of tofacitinib exposure, for an incident rate (IR) of 4.0 per 100 patient-years. However, IRs varied by region, ranging from 2.4 in Eastern Europe to 8.0 and 8.4 in Japan and Korea, respectively.
Further, in phase 3 studies, the IRs varied by tofacitinib dose, background use of conventional csDMARDs, and baseline glucocorticoid use; the rates were lowest among patients on tofacitinib monotherapy at a dose of 5 mg twice daily (IR, 0.6), and highest in those on tofacitinib at 10 mg twice daily with csDMARDs and glucocorticoids (IR, 5.4), the investigators found.
Independent risk factors for HZ included age, glucocorticoid use, tofacitinib dose, and enrollment within Asia, they said.
“Shingles, or reactivation of varicella virus, is a common and potentially debilitating illness. Around one-third of the general population will develop HZ in their lifetime, and approximately 10% of these patients develop postherpetic neuralgia which can last months to years and cause significant pain and morbidity,” the investigators wrote, adding that RA patients are at 1.5- to 2-fold greater risk vs. similarly aged individuals in the general population.
RA itself and treatment with glucocorticoids are known to increase HZ risk, but recent data have suggested that Janus kinase inhibitors, such as tofacitinib, and tumor necrosis factor antagonists are also associated with a higher rate of HZ. Additionally, a theoretical risk exists with various csDMARDs, they said.
“Given the increased risk of HZ observed among patients with RA versus the general population and the risk associated with RA therapies, it is possible that risk of HZ may be further increased when such therapies are combined,” they wrote.
Indeed, the findings of the study demonstrate an increased risk of HZ with tofacitinib in combination with glucocorticoids vs. tofacitinib monotherapy.
Further research is necessary to understand why Japanese and Korean patients are at elevated risk, and to understand the mechanism for the effects of combination therapy on VZV reactivation, they concluded.
LZV immunogenicity holds up during tofacitinib treatment
In the second study, 112 patients aged 50 years and older with active RA on background methotrexate received LZV and were then randomized to receive 5 mg tofacitinib twice daily or placebo 2-3 weeks after vaccination.
At 6 weeks after vaccination, VZV-specific IgG geometric mean fold rise (GMFR) was 2.11 and 1.74 in the tofacitinib and placebo patients, respectively; at all postvaccination time points at which VZV-specific IgG levels were evaluated, there was a trend toward numerically higher GMFR in tofacitinib patients, but the differences were not statistically significant. Also, the proportion of patients developing a 1.5-fold or greater postvaccination rise in IgG levels at 6 weeks trended higher for tofacitinib (57.4% vs. 43.4% with placebo).
VZV-specific T-cell GMFR at 6 weeks increased similarly in the groups (1.50 with tofacitinib and 1.29 with placebo).
Serious adverse events occurred in three patients in the tofacitinib group (5.5%) and in none of the placebo patients.
“The three SAEs included one case each of cholangitis and bronchitis, and once case of disseminated primary varicella,” the investigators said, noting that the onset of the latter was 16 days postvaccination, 2 days after starting tofacitinib. The rash resolved with discontinuation of tofacitinib and treatment with valacyclovir for 7 days.
The findings suggest that patients with active RA develop robust immune responses to HZ vaccine, and that starting tofacitinib 2-3 weeks after vaccination has no negative impact on the established immune response.
“Importantly, while our results suggest the vaccine is safe for patients with RA with prior VZV exposure, they also indicate the potential need to either screen for prior exposure before giving this vaccine or waiting longer than 2-3 weeks before starting immunosuppression with tofacitinib,” they said, noting that the current data suggest 4 weeks might be preferable.
Alternatively, testing patients who don’t recollect a history of chickenpox to ensure prior VZV exposure prior to vaccination could also mitigate the risk, they said.
“Further research is necessary to understand the risk of this complication, as well as the long-term effectiveness of this vaccine to prevent HZ in this high-risk population,” they concluded.
Both studies were sponsored by Pfizer. Dr. Winthrop has received research grants from and served as a scientific consultant to Pfizer. Other authors also reported financial relationships with Pfizer.
At a symposium during the 2015 annual meeting of the American College of Rheumatology, William Schaffner, MD, highlighted the connection between the seriousness of an infection, and the respect one has for the solution.
Dr. Schaffner said that “if you don’t fear the infection, you won’t value the solution.” Herpes zoster (HZ) should be feared, and the solution – the live zoster vaccine – valued.
Live zoster vaccine (LZV) was approved in 2006 on the basis of a trial involving more than 38,500 adults over age 60 years, which showed a 51% HZ prevention rate (64% protection in the 60-69 year age group) and a two-thirds reduction in postherpetic neuralgia. Complications and disseminated infection were rare.
HZ vaccination should be offered regardless of a history of varicella infection or prior shingles, as HZ may recur.
There is an imperative need to know who is at risk, when and how they should be vaccinated, and what other risk reduction measures should be considered.
John J. Cush, MD, is director of clinical rheumatology at Baylor Scott & White Research Institute and professor of medicine and rheumatology at Baylor University Medical Center, both in Dallas. His comments are taken from his editorial accompanying the two studies by Winthrop et al. (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40188).
At a symposium during the 2015 annual meeting of the American College of Rheumatology, William Schaffner, MD, highlighted the connection between the seriousness of an infection, and the respect one has for the solution.
Dr. Schaffner said that “if you don’t fear the infection, you won’t value the solution.” Herpes zoster (HZ) should be feared, and the solution – the live zoster vaccine – valued.
Live zoster vaccine (LZV) was approved in 2006 on the basis of a trial involving more than 38,500 adults over age 60 years, which showed a 51% HZ prevention rate (64% protection in the 60-69 year age group) and a two-thirds reduction in postherpetic neuralgia. Complications and disseminated infection were rare.
HZ vaccination should be offered regardless of a history of varicella infection or prior shingles, as HZ may recur.
There is an imperative need to know who is at risk, when and how they should be vaccinated, and what other risk reduction measures should be considered.
John J. Cush, MD, is director of clinical rheumatology at Baylor Scott & White Research Institute and professor of medicine and rheumatology at Baylor University Medical Center, both in Dallas. His comments are taken from his editorial accompanying the two studies by Winthrop et al. (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40188).
At a symposium during the 2015 annual meeting of the American College of Rheumatology, William Schaffner, MD, highlighted the connection between the seriousness of an infection, and the respect one has for the solution.
Dr. Schaffner said that “if you don’t fear the infection, you won’t value the solution.” Herpes zoster (HZ) should be feared, and the solution – the live zoster vaccine – valued.
Live zoster vaccine (LZV) was approved in 2006 on the basis of a trial involving more than 38,500 adults over age 60 years, which showed a 51% HZ prevention rate (64% protection in the 60-69 year age group) and a two-thirds reduction in postherpetic neuralgia. Complications and disseminated infection were rare.
HZ vaccination should be offered regardless of a history of varicella infection or prior shingles, as HZ may recur.
There is an imperative need to know who is at risk, when and how they should be vaccinated, and what other risk reduction measures should be considered.
John J. Cush, MD, is director of clinical rheumatology at Baylor Scott & White Research Institute and professor of medicine and rheumatology at Baylor University Medical Center, both in Dallas. His comments are taken from his editorial accompanying the two studies by Winthrop et al. (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40188).
The results of two studies of tofacitinib treatment for rheumatoid arthritis offer evidence to support the use of the drug without concomitant conventional synthetic disease-modifying antirheumatic drugs in order to reduce the risk of risk of herpes zoster infection and the safety of starting the drug 2-3 weeks after administering live zoster vaccine.
The risk of herpes zoster infection was elevated among rheumatoid arthritis (RA) patients receiving tofacitinib (Xeljanz) with glucocorticoids, compared with those receiving tofacitinib monotherapy, according to an analysis of data from 19 phase 2, phase 3, and long-term extension studies of tofacitinib.
“Further, physicians should continue to consider shingles vaccination prior to starting tofacitinib or biologic therapy,” they wrote.
Dr. Winthrop is the first author of a separate phase 2 study that also appears in Arthritis & Rheumatology, which suggests that live zoster vaccine (LZV) is safe in RA patients who start tofacitinib 2-3 weeks after vaccination. The study also showed that varicella-zoster virus (VZV)-specific humoral and cell-mediated immune responses to LZV are similar in tofacitinib- and placebo-treated patients.
“Our study provides the first data with this vaccine in the RA setting and suggests that these patients, even while using nonbiologic DMARDs at the time of vaccination, are capable of mounting adequate immune responses to this vaccine. Further, our data suggest that the use of tofacitinib following VZV vaccination in the RA setting did not impact negatively the vaccine immunogenicity or the time course of the immune response to the vaccine,” he and his colleagues wrote (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40187).
Increased herpes zoster risk in combination therapy
In the first study, herpes zoster (HZ) was reported in 636 of 6,192 patients over a median follow-up of 3 years of tofacitinib exposure, for an incident rate (IR) of 4.0 per 100 patient-years. However, IRs varied by region, ranging from 2.4 in Eastern Europe to 8.0 and 8.4 in Japan and Korea, respectively.
Further, in phase 3 studies, the IRs varied by tofacitinib dose, background use of conventional csDMARDs, and baseline glucocorticoid use; the rates were lowest among patients on tofacitinib monotherapy at a dose of 5 mg twice daily (IR, 0.6), and highest in those on tofacitinib at 10 mg twice daily with csDMARDs and glucocorticoids (IR, 5.4), the investigators found.
Independent risk factors for HZ included age, glucocorticoid use, tofacitinib dose, and enrollment within Asia, they said.
“Shingles, or reactivation of varicella virus, is a common and potentially debilitating illness. Around one-third of the general population will develop HZ in their lifetime, and approximately 10% of these patients develop postherpetic neuralgia which can last months to years and cause significant pain and morbidity,” the investigators wrote, adding that RA patients are at 1.5- to 2-fold greater risk vs. similarly aged individuals in the general population.
RA itself and treatment with glucocorticoids are known to increase HZ risk, but recent data have suggested that Janus kinase inhibitors, such as tofacitinib, and tumor necrosis factor antagonists are also associated with a higher rate of HZ. Additionally, a theoretical risk exists with various csDMARDs, they said.
“Given the increased risk of HZ observed among patients with RA versus the general population and the risk associated with RA therapies, it is possible that risk of HZ may be further increased when such therapies are combined,” they wrote.
Indeed, the findings of the study demonstrate an increased risk of HZ with tofacitinib in combination with glucocorticoids vs. tofacitinib monotherapy.
Further research is necessary to understand why Japanese and Korean patients are at elevated risk, and to understand the mechanism for the effects of combination therapy on VZV reactivation, they concluded.
LZV immunogenicity holds up during tofacitinib treatment
In the second study, 112 patients aged 50 years and older with active RA on background methotrexate received LZV and were then randomized to receive 5 mg tofacitinib twice daily or placebo 2-3 weeks after vaccination.
At 6 weeks after vaccination, VZV-specific IgG geometric mean fold rise (GMFR) was 2.11 and 1.74 in the tofacitinib and placebo patients, respectively; at all postvaccination time points at which VZV-specific IgG levels were evaluated, there was a trend toward numerically higher GMFR in tofacitinib patients, but the differences were not statistically significant. Also, the proportion of patients developing a 1.5-fold or greater postvaccination rise in IgG levels at 6 weeks trended higher for tofacitinib (57.4% vs. 43.4% with placebo).
VZV-specific T-cell GMFR at 6 weeks increased similarly in the groups (1.50 with tofacitinib and 1.29 with placebo).
Serious adverse events occurred in three patients in the tofacitinib group (5.5%) and in none of the placebo patients.
“The three SAEs included one case each of cholangitis and bronchitis, and once case of disseminated primary varicella,” the investigators said, noting that the onset of the latter was 16 days postvaccination, 2 days after starting tofacitinib. The rash resolved with discontinuation of tofacitinib and treatment with valacyclovir for 7 days.
The findings suggest that patients with active RA develop robust immune responses to HZ vaccine, and that starting tofacitinib 2-3 weeks after vaccination has no negative impact on the established immune response.
“Importantly, while our results suggest the vaccine is safe for patients with RA with prior VZV exposure, they also indicate the potential need to either screen for prior exposure before giving this vaccine or waiting longer than 2-3 weeks before starting immunosuppression with tofacitinib,” they said, noting that the current data suggest 4 weeks might be preferable.
Alternatively, testing patients who don’t recollect a history of chickenpox to ensure prior VZV exposure prior to vaccination could also mitigate the risk, they said.
“Further research is necessary to understand the risk of this complication, as well as the long-term effectiveness of this vaccine to prevent HZ in this high-risk population,” they concluded.
Both studies were sponsored by Pfizer. Dr. Winthrop has received research grants from and served as a scientific consultant to Pfizer. Other authors also reported financial relationships with Pfizer.
The results of two studies of tofacitinib treatment for rheumatoid arthritis offer evidence to support the use of the drug without concomitant conventional synthetic disease-modifying antirheumatic drugs in order to reduce the risk of risk of herpes zoster infection and the safety of starting the drug 2-3 weeks after administering live zoster vaccine.
The risk of herpes zoster infection was elevated among rheumatoid arthritis (RA) patients receiving tofacitinib (Xeljanz) with glucocorticoids, compared with those receiving tofacitinib monotherapy, according to an analysis of data from 19 phase 2, phase 3, and long-term extension studies of tofacitinib.
“Further, physicians should continue to consider shingles vaccination prior to starting tofacitinib or biologic therapy,” they wrote.
Dr. Winthrop is the first author of a separate phase 2 study that also appears in Arthritis & Rheumatology, which suggests that live zoster vaccine (LZV) is safe in RA patients who start tofacitinib 2-3 weeks after vaccination. The study also showed that varicella-zoster virus (VZV)-specific humoral and cell-mediated immune responses to LZV are similar in tofacitinib- and placebo-treated patients.
“Our study provides the first data with this vaccine in the RA setting and suggests that these patients, even while using nonbiologic DMARDs at the time of vaccination, are capable of mounting adequate immune responses to this vaccine. Further, our data suggest that the use of tofacitinib following VZV vaccination in the RA setting did not impact negatively the vaccine immunogenicity or the time course of the immune response to the vaccine,” he and his colleagues wrote (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40187).
Increased herpes zoster risk in combination therapy
In the first study, herpes zoster (HZ) was reported in 636 of 6,192 patients over a median follow-up of 3 years of tofacitinib exposure, for an incident rate (IR) of 4.0 per 100 patient-years. However, IRs varied by region, ranging from 2.4 in Eastern Europe to 8.0 and 8.4 in Japan and Korea, respectively.
Further, in phase 3 studies, the IRs varied by tofacitinib dose, background use of conventional csDMARDs, and baseline glucocorticoid use; the rates were lowest among patients on tofacitinib monotherapy at a dose of 5 mg twice daily (IR, 0.6), and highest in those on tofacitinib at 10 mg twice daily with csDMARDs and glucocorticoids (IR, 5.4), the investigators found.
Independent risk factors for HZ included age, glucocorticoid use, tofacitinib dose, and enrollment within Asia, they said.
“Shingles, or reactivation of varicella virus, is a common and potentially debilitating illness. Around one-third of the general population will develop HZ in their lifetime, and approximately 10% of these patients develop postherpetic neuralgia which can last months to years and cause significant pain and morbidity,” the investigators wrote, adding that RA patients are at 1.5- to 2-fold greater risk vs. similarly aged individuals in the general population.
RA itself and treatment with glucocorticoids are known to increase HZ risk, but recent data have suggested that Janus kinase inhibitors, such as tofacitinib, and tumor necrosis factor antagonists are also associated with a higher rate of HZ. Additionally, a theoretical risk exists with various csDMARDs, they said.
“Given the increased risk of HZ observed among patients with RA versus the general population and the risk associated with RA therapies, it is possible that risk of HZ may be further increased when such therapies are combined,” they wrote.
Indeed, the findings of the study demonstrate an increased risk of HZ with tofacitinib in combination with glucocorticoids vs. tofacitinib monotherapy.
Further research is necessary to understand why Japanese and Korean patients are at elevated risk, and to understand the mechanism for the effects of combination therapy on VZV reactivation, they concluded.
LZV immunogenicity holds up during tofacitinib treatment
In the second study, 112 patients aged 50 years and older with active RA on background methotrexate received LZV and were then randomized to receive 5 mg tofacitinib twice daily or placebo 2-3 weeks after vaccination.
At 6 weeks after vaccination, VZV-specific IgG geometric mean fold rise (GMFR) was 2.11 and 1.74 in the tofacitinib and placebo patients, respectively; at all postvaccination time points at which VZV-specific IgG levels were evaluated, there was a trend toward numerically higher GMFR in tofacitinib patients, but the differences were not statistically significant. Also, the proportion of patients developing a 1.5-fold or greater postvaccination rise in IgG levels at 6 weeks trended higher for tofacitinib (57.4% vs. 43.4% with placebo).
VZV-specific T-cell GMFR at 6 weeks increased similarly in the groups (1.50 with tofacitinib and 1.29 with placebo).
Serious adverse events occurred in three patients in the tofacitinib group (5.5%) and in none of the placebo patients.
“The three SAEs included one case each of cholangitis and bronchitis, and once case of disseminated primary varicella,” the investigators said, noting that the onset of the latter was 16 days postvaccination, 2 days after starting tofacitinib. The rash resolved with discontinuation of tofacitinib and treatment with valacyclovir for 7 days.
The findings suggest that patients with active RA develop robust immune responses to HZ vaccine, and that starting tofacitinib 2-3 weeks after vaccination has no negative impact on the established immune response.
“Importantly, while our results suggest the vaccine is safe for patients with RA with prior VZV exposure, they also indicate the potential need to either screen for prior exposure before giving this vaccine or waiting longer than 2-3 weeks before starting immunosuppression with tofacitinib,” they said, noting that the current data suggest 4 weeks might be preferable.
Alternatively, testing patients who don’t recollect a history of chickenpox to ensure prior VZV exposure prior to vaccination could also mitigate the risk, they said.
“Further research is necessary to understand the risk of this complication, as well as the long-term effectiveness of this vaccine to prevent HZ in this high-risk population,” they concluded.
Both studies were sponsored by Pfizer. Dr. Winthrop has received research grants from and served as a scientific consultant to Pfizer. Other authors also reported financial relationships with Pfizer.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Major finding: HZ rates were lowest among patients on tofacitinib monotherapy at a dose of 5 mg twice daily (IR, 0.6).
Data source: A phase 2 trial of 112 patients, and a review of 19 studies involving 6,192 patients.
Disclosures: Both studies were sponsored by Pfizer. Dr. Winthrop has received research grants from and served as a scientific consultant to Pfizer. Other authors also reported financial relationships with Pfizer.
FDA alert: pembrolizumab ups mortality risk in multiple myeloma
The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.
The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.
Among 249 patients in KEYNOTE-183, which evaluated pomalidomide and low-dose dexamethasone with or without pembrolizumab in patients with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy, the relative risk of death was increased more than 50% among those in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 1.61).
Among 301 patients in KEYNOTE-185, which evaluated lenalidomide and low-dose dexamethasone with or without pembrolizumab in patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant, the relative risk of death was nearly doubled in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 2.06).
“On July 3, 2017, the FDA required that all patients in these trials be discontinued from further investigation with this drug, because interim results from both trials demonstrated an increased risk of death for patients receiving Keytruda when it was combined with an immunomodulatory agent as compared to the control group,” according to the statement. “Merck & Co., Inc. [the maker of Keytruda] was made aware of the issue through an external data monitoring committee recommendation and suspended the trials to enrollment on June 12, 2017.”
The FDA statement and actions by Merck do not apply to patients using the drug for approved indications, which include melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high (MSI-H) cancer.
“Patients on Keytruda for an approved use should continue to take their medication as directed by their health care professional,” according to the FDA, which noted in its statement that the agency will be working directly with sponsors and investigators of other ongoing trials of the drug and other PD-1/PD-L1 cancer drugs to “determine the extent of safety issues.”
In a separate statement, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research further stressed that the FDA is “actively examining the data from the Keytruda trials and working directly with Merck to better understand the true cause of the safety concerns.”
“The FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and clinical trial researchers understand the risks associated with this investigational use. We are communicating now, given the serious nature of the safety issue, to remind doctors and patients that Keytruda is not approved for the treatment of multiple myeloma and should not be given to patients in combination with any immunomodulatory agents, including Revlimid (lenalidomide) and Pomalyst (pomalidomide), for the treatment of multiple myeloma,” she said.
Health care professionals and consumers are encouraged to report adverse events and side effects related to Keytruda or similar product to FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch/report, or by calling 800-332-1088 to request a reporting form.
sworcester@frontlinemedcom.com
The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.
The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.
Among 249 patients in KEYNOTE-183, which evaluated pomalidomide and low-dose dexamethasone with or without pembrolizumab in patients with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy, the relative risk of death was increased more than 50% among those in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 1.61).
Among 301 patients in KEYNOTE-185, which evaluated lenalidomide and low-dose dexamethasone with or without pembrolizumab in patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant, the relative risk of death was nearly doubled in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 2.06).
“On July 3, 2017, the FDA required that all patients in these trials be discontinued from further investigation with this drug, because interim results from both trials demonstrated an increased risk of death for patients receiving Keytruda when it was combined with an immunomodulatory agent as compared to the control group,” according to the statement. “Merck & Co., Inc. [the maker of Keytruda] was made aware of the issue through an external data monitoring committee recommendation and suspended the trials to enrollment on June 12, 2017.”
The FDA statement and actions by Merck do not apply to patients using the drug for approved indications, which include melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high (MSI-H) cancer.
“Patients on Keytruda for an approved use should continue to take their medication as directed by their health care professional,” according to the FDA, which noted in its statement that the agency will be working directly with sponsors and investigators of other ongoing trials of the drug and other PD-1/PD-L1 cancer drugs to “determine the extent of safety issues.”
In a separate statement, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research further stressed that the FDA is “actively examining the data from the Keytruda trials and working directly with Merck to better understand the true cause of the safety concerns.”
“The FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and clinical trial researchers understand the risks associated with this investigational use. We are communicating now, given the serious nature of the safety issue, to remind doctors and patients that Keytruda is not approved for the treatment of multiple myeloma and should not be given to patients in combination with any immunomodulatory agents, including Revlimid (lenalidomide) and Pomalyst (pomalidomide), for the treatment of multiple myeloma,” she said.
Health care professionals and consumers are encouraged to report adverse events and side effects related to Keytruda or similar product to FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch/report, or by calling 800-332-1088 to request a reporting form.
sworcester@frontlinemedcom.com
The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.
The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.
Among 249 patients in KEYNOTE-183, which evaluated pomalidomide and low-dose dexamethasone with or without pembrolizumab in patients with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy, the relative risk of death was increased more than 50% among those in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 1.61).
Among 301 patients in KEYNOTE-185, which evaluated lenalidomide and low-dose dexamethasone with or without pembrolizumab in patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant, the relative risk of death was nearly doubled in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 2.06).
“On July 3, 2017, the FDA required that all patients in these trials be discontinued from further investigation with this drug, because interim results from both trials demonstrated an increased risk of death for patients receiving Keytruda when it was combined with an immunomodulatory agent as compared to the control group,” according to the statement. “Merck & Co., Inc. [the maker of Keytruda] was made aware of the issue through an external data monitoring committee recommendation and suspended the trials to enrollment on June 12, 2017.”
The FDA statement and actions by Merck do not apply to patients using the drug for approved indications, which include melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high (MSI-H) cancer.
“Patients on Keytruda for an approved use should continue to take their medication as directed by their health care professional,” according to the FDA, which noted in its statement that the agency will be working directly with sponsors and investigators of other ongoing trials of the drug and other PD-1/PD-L1 cancer drugs to “determine the extent of safety issues.”
In a separate statement, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research further stressed that the FDA is “actively examining the data from the Keytruda trials and working directly with Merck to better understand the true cause of the safety concerns.”
“The FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and clinical trial researchers understand the risks associated with this investigational use. We are communicating now, given the serious nature of the safety issue, to remind doctors and patients that Keytruda is not approved for the treatment of multiple myeloma and should not be given to patients in combination with any immunomodulatory agents, including Revlimid (lenalidomide) and Pomalyst (pomalidomide), for the treatment of multiple myeloma,” she said.
Health care professionals and consumers are encouraged to report adverse events and side effects related to Keytruda or similar product to FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch/report, or by calling 800-332-1088 to request a reporting form.
sworcester@frontlinemedcom.com
Focus on lifestyle to manage menopause symptoms after breast cancer
Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.
The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.
“A large proportion of women experience menopausal symptoms or clinical manifestations of estrogen deficiency during treatment of their breast cancer or after completion of therapy. The specific symptoms and clinical challenges differ based on menopausal status prior to initiation of cancer treatment and therapeutic agents used,” the researchers wrote in a report published in the Journal of Clinical Endocrinology & Metabolism (2017 Aug 2. doi: 10.1210/jc.2017-01138).
For instance, among premenopausal women treated with chemotherapy, ovarian insufficiency, severe menopausal symptoms, and infertility can result. Postmenopasual women treated with aromatase inhibitors may experience arthralgia, accelerated bone loss, and osteoporotic fractures, as well as severe vulvovaginal atrophy, they explained, noting that both premenopausal and postmenopausal survivors can experience moderate-to-severe vasomotor symptoms and sleep disturbance with related fatigue, depressive symptoms, and mood changes.
“Less common problems include weight gain, symptomatic osteoarthritis and intervertebral disk degeneration, degenerative skin changes, radiation and chemotherapy-related cardiovascular disease, and reduced quality of life,” the researchers wrote.
Based on a review of randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies, the writing group concluded that individualized lifestyle modifications and nonpharmacologic therapies are recommended for the treatment of these symptoms.
Specifically, the writing group recommended smoking cessation, weight loss when indicated, limited alcohol intake, maintenance of adequate vitamin D and calcium levels, a healthy diet, and regular physical activity for all women with prior breast cancer.
They also recommended nonpharmacologic therapies for vasomotor symptoms, and noted that cognitive behavioral therapy, hypnosis, and acupuncture are among the approaches that may be helpful.
Vaginal lubricants and moisturizers can also be helpful for mild vulvovaginal atrophy, they wrote. For women with more severe symptoms or signs of estrogen deficiency, pharmacologic agents are available to relieve vasomotor symptoms and vulvovaginal atrophy, and to prevent and treat fractures, they wrote, adding that “therapy must be individualized based on each woman’s needs and goals for therapy.”
Among emerging approaches to treatment of symptoms are selective estrogen receptor modulators (SERMs), tissue selective estrogen complex (TSEC) therapy, estetrol, and neurokinin B inhibitors, which show promise for expanding options for symptom relief with less breast cancer risk. However, these have not yet been tested in women with prior breast cancer, the researchers noted.
Dr. Santen reported receiving research funding from Panterhei Bioscience. Other authors received research funding from Therapeutics MD and Lawley Pharmaceuticals, and honoraria from Abbott, Besins Health Care, and Pfizer.
Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.
The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.
“A large proportion of women experience menopausal symptoms or clinical manifestations of estrogen deficiency during treatment of their breast cancer or after completion of therapy. The specific symptoms and clinical challenges differ based on menopausal status prior to initiation of cancer treatment and therapeutic agents used,” the researchers wrote in a report published in the Journal of Clinical Endocrinology & Metabolism (2017 Aug 2. doi: 10.1210/jc.2017-01138).
For instance, among premenopausal women treated with chemotherapy, ovarian insufficiency, severe menopausal symptoms, and infertility can result. Postmenopasual women treated with aromatase inhibitors may experience arthralgia, accelerated bone loss, and osteoporotic fractures, as well as severe vulvovaginal atrophy, they explained, noting that both premenopausal and postmenopausal survivors can experience moderate-to-severe vasomotor symptoms and sleep disturbance with related fatigue, depressive symptoms, and mood changes.
“Less common problems include weight gain, symptomatic osteoarthritis and intervertebral disk degeneration, degenerative skin changes, radiation and chemotherapy-related cardiovascular disease, and reduced quality of life,” the researchers wrote.
Based on a review of randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies, the writing group concluded that individualized lifestyle modifications and nonpharmacologic therapies are recommended for the treatment of these symptoms.
Specifically, the writing group recommended smoking cessation, weight loss when indicated, limited alcohol intake, maintenance of adequate vitamin D and calcium levels, a healthy diet, and regular physical activity for all women with prior breast cancer.
They also recommended nonpharmacologic therapies for vasomotor symptoms, and noted that cognitive behavioral therapy, hypnosis, and acupuncture are among the approaches that may be helpful.
Vaginal lubricants and moisturizers can also be helpful for mild vulvovaginal atrophy, they wrote. For women with more severe symptoms or signs of estrogen deficiency, pharmacologic agents are available to relieve vasomotor symptoms and vulvovaginal atrophy, and to prevent and treat fractures, they wrote, adding that “therapy must be individualized based on each woman’s needs and goals for therapy.”
Among emerging approaches to treatment of symptoms are selective estrogen receptor modulators (SERMs), tissue selective estrogen complex (TSEC) therapy, estetrol, and neurokinin B inhibitors, which show promise for expanding options for symptom relief with less breast cancer risk. However, these have not yet been tested in women with prior breast cancer, the researchers noted.
Dr. Santen reported receiving research funding from Panterhei Bioscience. Other authors received research funding from Therapeutics MD and Lawley Pharmaceuticals, and honoraria from Abbott, Besins Health Care, and Pfizer.
Lifestyle modification, rather than hormone therapy, should form the basis for managing estrogen-depletion symptoms and associated clinical problems in breast cancer survivors, according to a review of available evidence.
The review, conducted by the writing group for the Endocrine Society’s guidelines on management of menopausal symptoms, was prompted by the paucity of both randomized controlled trials in breast cancer survivors with estrogen deficiency issues and guidelines that sufficiently focus on treatment of this subgroup of women.
“A large proportion of women experience menopausal symptoms or clinical manifestations of estrogen deficiency during treatment of their breast cancer or after completion of therapy. The specific symptoms and clinical challenges differ based on menopausal status prior to initiation of cancer treatment and therapeutic agents used,” the researchers wrote in a report published in the Journal of Clinical Endocrinology & Metabolism (2017 Aug 2. doi: 10.1210/jc.2017-01138).
For instance, among premenopausal women treated with chemotherapy, ovarian insufficiency, severe menopausal symptoms, and infertility can result. Postmenopasual women treated with aromatase inhibitors may experience arthralgia, accelerated bone loss, and osteoporotic fractures, as well as severe vulvovaginal atrophy, they explained, noting that both premenopausal and postmenopausal survivors can experience moderate-to-severe vasomotor symptoms and sleep disturbance with related fatigue, depressive symptoms, and mood changes.
“Less common problems include weight gain, symptomatic osteoarthritis and intervertebral disk degeneration, degenerative skin changes, radiation and chemotherapy-related cardiovascular disease, and reduced quality of life,” the researchers wrote.
Based on a review of randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies, the writing group concluded that individualized lifestyle modifications and nonpharmacologic therapies are recommended for the treatment of these symptoms.
Specifically, the writing group recommended smoking cessation, weight loss when indicated, limited alcohol intake, maintenance of adequate vitamin D and calcium levels, a healthy diet, and regular physical activity for all women with prior breast cancer.
They also recommended nonpharmacologic therapies for vasomotor symptoms, and noted that cognitive behavioral therapy, hypnosis, and acupuncture are among the approaches that may be helpful.
Vaginal lubricants and moisturizers can also be helpful for mild vulvovaginal atrophy, they wrote. For women with more severe symptoms or signs of estrogen deficiency, pharmacologic agents are available to relieve vasomotor symptoms and vulvovaginal atrophy, and to prevent and treat fractures, they wrote, adding that “therapy must be individualized based on each woman’s needs and goals for therapy.”
Among emerging approaches to treatment of symptoms are selective estrogen receptor modulators (SERMs), tissue selective estrogen complex (TSEC) therapy, estetrol, and neurokinin B inhibitors, which show promise for expanding options for symptom relief with less breast cancer risk. However, these have not yet been tested in women with prior breast cancer, the researchers noted.
Dr. Santen reported receiving research funding from Panterhei Bioscience. Other authors received research funding from Therapeutics MD and Lawley Pharmaceuticals, and honoraria from Abbott, Besins Health Care, and Pfizer.
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
FDA approves first gene therapy – tisagenlecleucel for ALL
The U.S. Food and Drug Administration has approved tisagenlecleucel (Kymriah), a first-of-its-kind chimeric antigen receptor T-cell (CAR T) therapy, for the treatment of children and young adults up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
Tisagenlecleucel will carry a boxed warning regarding the CRS risk. Additionally, due to the CRS risk and risk of neurological events, the approval requires a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, according to an FDA press release.
Special certification will be required for hospitals and associated clinics that dispense tisagenlecleucel. As part of certification, staff will be trained in the prescribing, dispensing, or administering of the therapy, and to recognize and manage CRS and neurological events.
Novartis, the maker of tisagenlecleucel, will be required to conduct postmarketing observational study.
Indeed, FDA commissioner Scott Gottlieb, MD, said the approval marks the entry to a “new frontier in medical innovation.”
“New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses,” he said in the press statement.
Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy involving customized treatment created using a patient’s own T cells. The T cells are genetically modified to include a chimeric antigen receptor that directs the T cells to target and kill leukemia cells with CD19 surface antigen, and are then infused back into the patient.
In a phase 2 clinical trial, the overall remission rate with tisagenlecleucel therapy was 83% in 63 children and young adults with relapsed/refractory B-cell precursor ALL for whom at least two prior lines of therapy had failed; the therapy was granted Fast Track, Priority Review, and Breakthrough Therapy designations.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research said in the press statement.
“Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that shows promising remission and survival rates in clinical trials.”
At its meeting in July, the FDA ODAC agreed nearly unanimously that the risk mitigation plan put forward by Novartis, including planned 15-year follow-up and other mitigation measures, would be adequate for detecting serious consequences of CAR T-cell therapy.
sworcester@frontlinemedcom.com
This article was updated August 30, 2017.
The U.S. Food and Drug Administration has approved tisagenlecleucel (Kymriah), a first-of-its-kind chimeric antigen receptor T-cell (CAR T) therapy, for the treatment of children and young adults up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
Tisagenlecleucel will carry a boxed warning regarding the CRS risk. Additionally, due to the CRS risk and risk of neurological events, the approval requires a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, according to an FDA press release.
Special certification will be required for hospitals and associated clinics that dispense tisagenlecleucel. As part of certification, staff will be trained in the prescribing, dispensing, or administering of the therapy, and to recognize and manage CRS and neurological events.
Novartis, the maker of tisagenlecleucel, will be required to conduct postmarketing observational study.
Indeed, FDA commissioner Scott Gottlieb, MD, said the approval marks the entry to a “new frontier in medical innovation.”
“New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses,” he said in the press statement.
Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy involving customized treatment created using a patient’s own T cells. The T cells are genetically modified to include a chimeric antigen receptor that directs the T cells to target and kill leukemia cells with CD19 surface antigen, and are then infused back into the patient.
In a phase 2 clinical trial, the overall remission rate with tisagenlecleucel therapy was 83% in 63 children and young adults with relapsed/refractory B-cell precursor ALL for whom at least two prior lines of therapy had failed; the therapy was granted Fast Track, Priority Review, and Breakthrough Therapy designations.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research said in the press statement.
“Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that shows promising remission and survival rates in clinical trials.”
At its meeting in July, the FDA ODAC agreed nearly unanimously that the risk mitigation plan put forward by Novartis, including planned 15-year follow-up and other mitigation measures, would be adequate for detecting serious consequences of CAR T-cell therapy.
sworcester@frontlinemedcom.com
This article was updated August 30, 2017.
The U.S. Food and Drug Administration has approved tisagenlecleucel (Kymriah), a first-of-its-kind chimeric antigen receptor T-cell (CAR T) therapy, for the treatment of children and young adults up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
Tisagenlecleucel will carry a boxed warning regarding the CRS risk. Additionally, due to the CRS risk and risk of neurological events, the approval requires a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, according to an FDA press release.
Special certification will be required for hospitals and associated clinics that dispense tisagenlecleucel. As part of certification, staff will be trained in the prescribing, dispensing, or administering of the therapy, and to recognize and manage CRS and neurological events.
Novartis, the maker of tisagenlecleucel, will be required to conduct postmarketing observational study.
Indeed, FDA commissioner Scott Gottlieb, MD, said the approval marks the entry to a “new frontier in medical innovation.”
“New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses,” he said in the press statement.
Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy involving customized treatment created using a patient’s own T cells. The T cells are genetically modified to include a chimeric antigen receptor that directs the T cells to target and kill leukemia cells with CD19 surface antigen, and are then infused back into the patient.
In a phase 2 clinical trial, the overall remission rate with tisagenlecleucel therapy was 83% in 63 children and young adults with relapsed/refractory B-cell precursor ALL for whom at least two prior lines of therapy had failed; the therapy was granted Fast Track, Priority Review, and Breakthrough Therapy designations.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research said in the press statement.
“Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that shows promising remission and survival rates in clinical trials.”
At its meeting in July, the FDA ODAC agreed nearly unanimously that the risk mitigation plan put forward by Novartis, including planned 15-year follow-up and other mitigation measures, would be adequate for detecting serious consequences of CAR T-cell therapy.
sworcester@frontlinemedcom.com
This article was updated August 30, 2017.
The opioid crisis: Psychiatrists are well equipped to intervene
The U.S. opioid crisis and ongoing epidemic of chronic pain are inextricably intertwined, and psychiatrists are increasingly being called upon to intervene.
In a June 2016 blog post penned in the wake of new Centers for Disease Control and Prevention prescribing guidelines calling for a move away from opioids as the first-line treatment for many types of chronic noncancer pain, National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, decried the absence of psychiatrists on the front lines.
“Thus far, psychiatrists have not taken an active role in addressing the problem of chronic pain, but they have an important role to play here, for multiple reasons,” she wrote.
Chronic pain is closely linked to multiple psychiatric problems, she explained.
Furthermore, extensive evidence supports the use of some nonpharmacologic psychiatric therapies, she noted.
Indeed, there are numerous approaches, which have been shown to be effective or are showing promise in trials, that psychiatrists can take to intervene in the crisis and to help individual patients control pain and reduce the need for opioid medication. One that is underused and undervalued despite decades of research demonstrating its effectiveness, and which, according to David Spiegel, MD, has the potential to help at least two-thirds of affected adults, is hypnosis.
Power of hypnosis
“The brain has a whole lot to do with pain perception, and there’s a lot you can do to control it,” said Dr. Spiegel, the Jack, Samuel, and Lulu Willson Professor in Medicine in the department of psychiatry and behavioral sciences at Stanford (Calif.) University and a member of the Institute of Medicine.
And despite what many patients and physicians believe, it’s simply not true that if you’re not using a drug, you can’t actually control pain, he added.
For example, in a prospective randomized study of 241 patients undergoing percutaneous vascular and renal procedures, he and his colleagues found that self-hypnotic relaxation was superior to both intraoperative standard of care and structured attention (i.e., the “friendly nurse” group) for reducing pain and anxiety, and was better than standard of care for reducing drug use and reducing procedure time. It also improved hemodynamic stability compared with the other approaches (Lancet. 2000 Apr 29;355[9214]:1486-90).
“It works,” said Dr. Spiegel, also associate chair of the psychiatry department at Stanford.
Hypnotizability can be assessed using various validated scales; he said he can determine hypnotizability within 5 minutes, in part by giving a suggestion that the patient’s arm is getting lighter and is beginning to float. A component of involuntariness – if the patient’s arm feels like it is floating effortlessly and actually moves up in the air – indicates hypnotizability.
Most children, and about two of every three adults, can be hypnotized, he said.
Self-hypnosis, particularly in the chronic pain setting, can be life-changing, as patients can use it whenever needed once they learn how, he said, describing one young patient who had been suffering from intractable migraines and associated vomiting for years, and had failed to respond to numerous medications. Within minutes of being taught self-hypnosis, she said her pain had decreased from 7 to 3 on a 0-10 scale, and after coming out of the hypnotic state, she described feeling as rested as if she’d been sleeping for a decade.
Her mother broke down in tears of relief, Dr. Spiegel said.
Another patient who had suffered from immobilizing back pain had a similar experience: His back pain was immediately reduced by about 60% .
“Does it always work? No, but no treatment always works, and at worst it’s harmless,” Dr. Spiegel said, adding: “I don’t get people addicted to hypnosis. It just doesn’t happen.”
So why is hypnosis still considered outside the mainstream? In part that’s the case because of its “purple cape, dangling watch” image, but there also is a conception that hypnosis takes away control. In reality, it enhances control, he said.
“I think every psychiatrist – every physician – should know hypnosis,” he said.
Many, but not all medical schools teach hypnosis, and at least two U.S. societies – the American Society of Clinical Hypnosis and the Society for Clinical and Experimental Hypnosis – conduct workshops and annual scientific meetings where those interested can learn, he noted.
“It’s not that hard to learn ... and it’s a very useful skill for a professional,” he said.
Other approaches to pain management
For the one in three adults who are not hypnotizable, Dr. Spiegel teaches distraction techniques, and sometimes recommends acupuncture, which can be helpful for some patients. Exercise and physical therapy also can be of benefit for chronic pain.
“You can have very real pain that you can learn to deal with as people did throughout history. That doesn’t mean you should suffer unnecessarily; there is a time and place for opiates and other [pharmacologic] strategies, but they should be one among an array of choices,” he said, adding that for chronic pain, opioids can be more of a problem than a solution, and learning these techniques “can really help people safely deal with pain.”
Jeffrey Borckardt, PhD, professor and director of the division of biobehavioral medicine at the Medical University of South Carolina (MUSC), Charleston, agreed that hypnosis is a well-researched and effective treatment for pain, despite being better known for weight loss and smoking cessation. Another, lesser-known treatment that has been shown to have some effect for pain is acceptance and commitment therapy, or ACT, which incorporates the practice of mindfulness. 
A 2014 study (J Pain. 2014 Jan;15[1]:101-13) demonstrated a beneficial effect of ACT in nearly 50% of patients studied, and in a 2017 study (J Pain. 2017 Jun;18[6]:664-72), ACT was associated with improved function in chronic pain patients.
However, there is another well-researched – and well-known – nonpharmacologic approach to the treatment of pain: cognitive-behavioral therapy, or CBT. CBT isn’t as new and exciting as some experimental approaches that Dr. Borckardt is working with and studying, such as transcranial magnetic stimulation and transcranial direct current stimulation. But CBT is readily available and typically covered by insurance (unlike those experimental therapies), and has been shown in numerous studies to be highly effective, he said.
CBT and ‘360’ programs
CBT also was mentioned by Dr. Volkow in her June 2016 blog post. She called it “one of the most effective pain treatments,” and said that “assisting patients in learning to change their pain-related thoughts, emotions, and behaviors is going to help with their condition, regardless of other pharmacological interventions.”
Dr. Borckardt said it is particularly effective in the context of programs that provide what he called “a 360 approach.” These multifaceted treatment programs aim to help chronic pain patients taper off of opioid medications and to find other approaches to managing pain.
Only a handful of such comprehensive, intensive outpatient programs exist across the United States, but the concept is taking hold, driven in part by the opioid crisis, and more centers are opening. In fact, Dr. Borckardt is helping to develop such a program at MUSC. The program will likely be housed in the MUSC Wellness Center, and much like the Mayo Clinic’s Pain Rehabilitation Center, which opened in 1974 and was one of the first such programs in the world, the MUSC program will involve an integrated team of health care professionals that provide CBT for pain, physical therapy, occupational therapy, and other programs designed to help patients living with pain.
This is widely accepted as being the best approach for pain rehabilitation, Dr. Borckardt said.
TMS and TDCS
Dr. Borckardt also has worked with some more cutting-edge approaches to pain management. Transcranial magnetic stimulation (TMS), which is approved for the treatment of depression, also has shown promise for treating pain. TMS can target areas in the brain involved with specific functioning, such as emotional regulation. The high-frequency stimulation is believed to enhance that particular area and produce a clinical effect.
“Pain is a subjective, largely psychological experience, and it involves an emotional component,” he said, explaining that the rationale for the use of TMS for pain is that the emotional component of the pain experience can be targeted along with the sensory and cognitive aspects of the pain experience.
TMS is being used in various studies, and has been used off label for pain management, but the out-of-pocket cost is high because it is not currently approved for pain and is therefore not covered by insurance, he said.
For depression, TMS typically is used 5 days per week for 3 weeks – at a cost ranging anywhere from $100 to $500 per session. It remains unclear how many sessions would be required for pain treatment to produce a sustained effect, but it would likely be similar to the requirements for depression treatment, and may also require follow-up treatments, Dr. Borckardt said.
“We do know with reasonable confidence that it impacts pain perception and can impact sensory or emotional components of pain, depending on the part of the brain treated. But we don’t know how long we have to treat, how often, or how durable the effects are,” he said, noting that several groups are studying TMS for pain.
Notably, there is also some very preliminary evidence that TMS may be useful for treating addiction by affecting cravings for substances such as opiates, nicotine, and alcohol. If that effect is confirmed, TMS could help chronic pain patients reduce their need for higher opioid doses, thereby lowering the risk of overdose, which is an important factor in the opioid crisis; most patients who use opioids don’t become addicted, but they can be at risk for overdose because of the need for high doses to control their pain, he explained.
In one study, the use of TMS postoperatively reduced the amount of in-hospital drug use by 40%, he said, noting that the reduction could convert to a reduction in the use of pain medication after discharge as well.
A related treatment, transcranial direct current stimulation, or tDCS, involves placement of electrodes directly on the scalp to run weak electrical currents through the brain, again trying to alter areas associated with pain perception. Ongoing studies are looking at combining tDCS and CBT with the hope that the two will have synergistic effects, including one in veterans with low back pain and opioid misuse. Another small pilot study in patients with fibromyalgia recently concluded and had some promising results.
These and other nonpharmacologic approaches to pain management could play an important role in the effort to reduce opioid prescribing. Currently, about 90 Americans die each day after overdosing on opioids, according to NIDA, and the CDC estimates that prescription opioid misuse alone in the United States costs $78.5 billion per year in health care, lost productivity, addiction treatment, and criminal justice involvement.
In her plea to psychiatrists to take action to intervene, Dr. Volkow underscored the value that they bring to the table.
“It is crucial that we not lose sight of the reality and complexity of chronic pain as management of chronic noncancer pain moves toward greater caution around opioid medication. This should not be solely an issue for primary care medicine or neurology, but also for specialties such as psychiatry that have much to offer people who are suffering from complex disorders in which physical symptoms merge with psychological distress,” she wrote.
Dr. Volkow has written hundreds of peer-reviewed articles, including analyses of the opioid crisis (N Engl J Med. 2017 Jul 27;377[4]:391-4) and (Neuron. 2016 Oct 19[2]:294-7). Dr. Spiegel is coauthor of Trance and Treatment: Clinical Uses of Hypnosis (Washington: American Psychiatric Association Publishing, 2004), a textbook written to help psychiatrists and other physicians learn to use hypnosis. Dr. Borckardt receives research funding from the National Institutes of Health.
The U.S. opioid crisis and ongoing epidemic of chronic pain are inextricably intertwined, and psychiatrists are increasingly being called upon to intervene.
In a June 2016 blog post penned in the wake of new Centers for Disease Control and Prevention prescribing guidelines calling for a move away from opioids as the first-line treatment for many types of chronic noncancer pain, National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, decried the absence of psychiatrists on the front lines.
“Thus far, psychiatrists have not taken an active role in addressing the problem of chronic pain, but they have an important role to play here, for multiple reasons,” she wrote.
Chronic pain is closely linked to multiple psychiatric problems, she explained.
Furthermore, extensive evidence supports the use of some nonpharmacologic psychiatric therapies, she noted.
Indeed, there are numerous approaches, which have been shown to be effective or are showing promise in trials, that psychiatrists can take to intervene in the crisis and to help individual patients control pain and reduce the need for opioid medication. One that is underused and undervalued despite decades of research demonstrating its effectiveness, and which, according to David Spiegel, MD, has the potential to help at least two-thirds of affected adults, is hypnosis.
Power of hypnosis
“The brain has a whole lot to do with pain perception, and there’s a lot you can do to control it,” said Dr. Spiegel, the Jack, Samuel, and Lulu Willson Professor in Medicine in the department of psychiatry and behavioral sciences at Stanford (Calif.) University and a member of the Institute of Medicine.
And despite what many patients and physicians believe, it’s simply not true that if you’re not using a drug, you can’t actually control pain, he added.
For example, in a prospective randomized study of 241 patients undergoing percutaneous vascular and renal procedures, he and his colleagues found that self-hypnotic relaxation was superior to both intraoperative standard of care and structured attention (i.e., the “friendly nurse” group) for reducing pain and anxiety, and was better than standard of care for reducing drug use and reducing procedure time. It also improved hemodynamic stability compared with the other approaches (Lancet. 2000 Apr 29;355[9214]:1486-90).
“It works,” said Dr. Spiegel, also associate chair of the psychiatry department at Stanford.
Hypnotizability can be assessed using various validated scales; he said he can determine hypnotizability within 5 minutes, in part by giving a suggestion that the patient’s arm is getting lighter and is beginning to float. A component of involuntariness – if the patient’s arm feels like it is floating effortlessly and actually moves up in the air – indicates hypnotizability.
Most children, and about two of every three adults, can be hypnotized, he said.
Self-hypnosis, particularly in the chronic pain setting, can be life-changing, as patients can use it whenever needed once they learn how, he said, describing one young patient who had been suffering from intractable migraines and associated vomiting for years, and had failed to respond to numerous medications. Within minutes of being taught self-hypnosis, she said her pain had decreased from 7 to 3 on a 0-10 scale, and after coming out of the hypnotic state, she described feeling as rested as if she’d been sleeping for a decade.
Her mother broke down in tears of relief, Dr. Spiegel said.
Another patient who had suffered from immobilizing back pain had a similar experience: His back pain was immediately reduced by about 60% .
“Does it always work? No, but no treatment always works, and at worst it’s harmless,” Dr. Spiegel said, adding: “I don’t get people addicted to hypnosis. It just doesn’t happen.”
So why is hypnosis still considered outside the mainstream? In part that’s the case because of its “purple cape, dangling watch” image, but there also is a conception that hypnosis takes away control. In reality, it enhances control, he said.
“I think every psychiatrist – every physician – should know hypnosis,” he said.
Many, but not all medical schools teach hypnosis, and at least two U.S. societies – the American Society of Clinical Hypnosis and the Society for Clinical and Experimental Hypnosis – conduct workshops and annual scientific meetings where those interested can learn, he noted.
“It’s not that hard to learn ... and it’s a very useful skill for a professional,” he said.
Other approaches to pain management
For the one in three adults who are not hypnotizable, Dr. Spiegel teaches distraction techniques, and sometimes recommends acupuncture, which can be helpful for some patients. Exercise and physical therapy also can be of benefit for chronic pain.
“You can have very real pain that you can learn to deal with as people did throughout history. That doesn’t mean you should suffer unnecessarily; there is a time and place for opiates and other [pharmacologic] strategies, but they should be one among an array of choices,” he said, adding that for chronic pain, opioids can be more of a problem than a solution, and learning these techniques “can really help people safely deal with pain.”
Jeffrey Borckardt, PhD, professor and director of the division of biobehavioral medicine at the Medical University of South Carolina (MUSC), Charleston, agreed that hypnosis is a well-researched and effective treatment for pain, despite being better known for weight loss and smoking cessation. Another, lesser-known treatment that has been shown to have some effect for pain is acceptance and commitment therapy, or ACT, which incorporates the practice of mindfulness.
A 2014 study (J Pain. 2014 Jan;15[1]:101-13) demonstrated a beneficial effect of ACT in nearly 50% of patients studied, and in a 2017 study (J Pain. 2017 Jun;18[6]:664-72), ACT was associated with improved function in chronic pain patients.
However, there is another well-researched – and well-known – nonpharmacologic approach to the treatment of pain: cognitive-behavioral therapy, or CBT. CBT isn’t as new and exciting as some experimental approaches that Dr. Borckardt is working with and studying, such as transcranial magnetic stimulation and transcranial direct current stimulation. But CBT is readily available and typically covered by insurance (unlike those experimental therapies), and has been shown in numerous studies to be highly effective, he said.
CBT and ‘360’ programs
CBT also was mentioned by Dr. Volkow in her June 2016 blog post. She called it “one of the most effective pain treatments,” and said that “assisting patients in learning to change their pain-related thoughts, emotions, and behaviors is going to help with their condition, regardless of other pharmacological interventions.”
Dr. Borckardt said it is particularly effective in the context of programs that provide what he called “a 360 approach.” These multifaceted treatment programs aim to help chronic pain patients taper off of opioid medications and to find other approaches to managing pain.
Only a handful of such comprehensive, intensive outpatient programs exist across the United States, but the concept is taking hold, driven in part by the opioid crisis, and more centers are opening. In fact, Dr. Borckardt is helping to develop such a program at MUSC. The program will likely be housed in the MUSC Wellness Center, and much like the Mayo Clinic’s Pain Rehabilitation Center, which opened in 1974 and was one of the first such programs in the world, the MUSC program will involve an integrated team of health care professionals that provide CBT for pain, physical therapy, occupational therapy, and other programs designed to help patients living with pain.
This is widely accepted as being the best approach for pain rehabilitation, Dr. Borckardt said.
TMS and TDCS
Dr. Borckardt also has worked with some more cutting-edge approaches to pain management. Transcranial magnetic stimulation (TMS), which is approved for the treatment of depression, also has shown promise for treating pain. TMS can target areas in the brain involved with specific functioning, such as emotional regulation. The high-frequency stimulation is believed to enhance that particular area and produce a clinical effect.
“Pain is a subjective, largely psychological experience, and it involves an emotional component,” he said, explaining that the rationale for the use of TMS for pain is that the emotional component of the pain experience can be targeted along with the sensory and cognitive aspects of the pain experience.
TMS is being used in various studies, and has been used off label for pain management, but the out-of-pocket cost is high because it is not currently approved for pain and is therefore not covered by insurance, he said.
For depression, TMS typically is used 5 days per week for 3 weeks – at a cost ranging anywhere from $100 to $500 per session. It remains unclear how many sessions would be required for pain treatment to produce a sustained effect, but it would likely be similar to the requirements for depression treatment, and may also require follow-up treatments, Dr. Borckardt said.
“We do know with reasonable confidence that it impacts pain perception and can impact sensory or emotional components of pain, depending on the part of the brain treated. But we don’t know how long we have to treat, how often, or how durable the effects are,” he said, noting that several groups are studying TMS for pain.
Notably, there is also some very preliminary evidence that TMS may be useful for treating addiction by affecting cravings for substances such as opiates, nicotine, and alcohol. If that effect is confirmed, TMS could help chronic pain patients reduce their need for higher opioid doses, thereby lowering the risk of overdose, which is an important factor in the opioid crisis; most patients who use opioids don’t become addicted, but they can be at risk for overdose because of the need for high doses to control their pain, he explained.
In one study, the use of TMS postoperatively reduced the amount of in-hospital drug use by 40%, he said, noting that the reduction could convert to a reduction in the use of pain medication after discharge as well.
A related treatment, transcranial direct current stimulation, or tDCS, involves placement of electrodes directly on the scalp to run weak electrical currents through the brain, again trying to alter areas associated with pain perception. Ongoing studies are looking at combining tDCS and CBT with the hope that the two will have synergistic effects, including one in veterans with low back pain and opioid misuse. Another small pilot study in patients with fibromyalgia recently concluded and had some promising results.
These and other nonpharmacologic approaches to pain management could play an important role in the effort to reduce opioid prescribing. Currently, about 90 Americans die each day after overdosing on opioids, according to NIDA, and the CDC estimates that prescription opioid misuse alone in the United States costs $78.5 billion per year in health care, lost productivity, addiction treatment, and criminal justice involvement.
In her plea to psychiatrists to take action to intervene, Dr. Volkow underscored the value that they bring to the table.
“It is crucial that we not lose sight of the reality and complexity of chronic pain as management of chronic noncancer pain moves toward greater caution around opioid medication. This should not be solely an issue for primary care medicine or neurology, but also for specialties such as psychiatry that have much to offer people who are suffering from complex disorders in which physical symptoms merge with psychological distress,” she wrote.
Dr. Volkow has written hundreds of peer-reviewed articles, including analyses of the opioid crisis (N Engl J Med. 2017 Jul 27;377[4]:391-4) and (Neuron. 2016 Oct 19[2]:294-7). Dr. Spiegel is coauthor of Trance and Treatment: Clinical Uses of Hypnosis (Washington: American Psychiatric Association Publishing, 2004), a textbook written to help psychiatrists and other physicians learn to use hypnosis. Dr. Borckardt receives research funding from the National Institutes of Health.
The U.S. opioid crisis and ongoing epidemic of chronic pain are inextricably intertwined, and psychiatrists are increasingly being called upon to intervene.
In a June 2016 blog post penned in the wake of new Centers for Disease Control and Prevention prescribing guidelines calling for a move away from opioids as the first-line treatment for many types of chronic noncancer pain, National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, decried the absence of psychiatrists on the front lines.
“Thus far, psychiatrists have not taken an active role in addressing the problem of chronic pain, but they have an important role to play here, for multiple reasons,” she wrote.
Chronic pain is closely linked to multiple psychiatric problems, she explained.
Furthermore, extensive evidence supports the use of some nonpharmacologic psychiatric therapies, she noted.
Indeed, there are numerous approaches, which have been shown to be effective or are showing promise in trials, that psychiatrists can take to intervene in the crisis and to help individual patients control pain and reduce the need for opioid medication. One that is underused and undervalued despite decades of research demonstrating its effectiveness, and which, according to David Spiegel, MD, has the potential to help at least two-thirds of affected adults, is hypnosis.
Power of hypnosis
“The brain has a whole lot to do with pain perception, and there’s a lot you can do to control it,” said Dr. Spiegel, the Jack, Samuel, and Lulu Willson Professor in Medicine in the department of psychiatry and behavioral sciences at Stanford (Calif.) University and a member of the Institute of Medicine.
And despite what many patients and physicians believe, it’s simply not true that if you’re not using a drug, you can’t actually control pain, he added.
For example, in a prospective randomized study of 241 patients undergoing percutaneous vascular and renal procedures, he and his colleagues found that self-hypnotic relaxation was superior to both intraoperative standard of care and structured attention (i.e., the “friendly nurse” group) for reducing pain and anxiety, and was better than standard of care for reducing drug use and reducing procedure time. It also improved hemodynamic stability compared with the other approaches (Lancet. 2000 Apr 29;355[9214]:1486-90).
“It works,” said Dr. Spiegel, also associate chair of the psychiatry department at Stanford.
Hypnotizability can be assessed using various validated scales; he said he can determine hypnotizability within 5 minutes, in part by giving a suggestion that the patient’s arm is getting lighter and is beginning to float. A component of involuntariness – if the patient’s arm feels like it is floating effortlessly and actually moves up in the air – indicates hypnotizability.
Most children, and about two of every three adults, can be hypnotized, he said.
Self-hypnosis, particularly in the chronic pain setting, can be life-changing, as patients can use it whenever needed once they learn how, he said, describing one young patient who had been suffering from intractable migraines and associated vomiting for years, and had failed to respond to numerous medications. Within minutes of being taught self-hypnosis, she said her pain had decreased from 7 to 3 on a 0-10 scale, and after coming out of the hypnotic state, she described feeling as rested as if she’d been sleeping for a decade.
Her mother broke down in tears of relief, Dr. Spiegel said.
Another patient who had suffered from immobilizing back pain had a similar experience: His back pain was immediately reduced by about 60% .
“Does it always work? No, but no treatment always works, and at worst it’s harmless,” Dr. Spiegel said, adding: “I don’t get people addicted to hypnosis. It just doesn’t happen.”
So why is hypnosis still considered outside the mainstream? In part that’s the case because of its “purple cape, dangling watch” image, but there also is a conception that hypnosis takes away control. In reality, it enhances control, he said.
“I think every psychiatrist – every physician – should know hypnosis,” he said.
Many, but not all medical schools teach hypnosis, and at least two U.S. societies – the American Society of Clinical Hypnosis and the Society for Clinical and Experimental Hypnosis – conduct workshops and annual scientific meetings where those interested can learn, he noted.
“It’s not that hard to learn ... and it’s a very useful skill for a professional,” he said.
Other approaches to pain management
For the one in three adults who are not hypnotizable, Dr. Spiegel teaches distraction techniques, and sometimes recommends acupuncture, which can be helpful for some patients. Exercise and physical therapy also can be of benefit for chronic pain.
“You can have very real pain that you can learn to deal with as people did throughout history. That doesn’t mean you should suffer unnecessarily; there is a time and place for opiates and other [pharmacologic] strategies, but they should be one among an array of choices,” he said, adding that for chronic pain, opioids can be more of a problem than a solution, and learning these techniques “can really help people safely deal with pain.”
Jeffrey Borckardt, PhD, professor and director of the division of biobehavioral medicine at the Medical University of South Carolina (MUSC), Charleston, agreed that hypnosis is a well-researched and effective treatment for pain, despite being better known for weight loss and smoking cessation. Another, lesser-known treatment that has been shown to have some effect for pain is acceptance and commitment therapy, or ACT, which incorporates the practice of mindfulness.
A 2014 study (J Pain. 2014 Jan;15[1]:101-13) demonstrated a beneficial effect of ACT in nearly 50% of patients studied, and in a 2017 study (J Pain. 2017 Jun;18[6]:664-72), ACT was associated with improved function in chronic pain patients.
However, there is another well-researched – and well-known – nonpharmacologic approach to the treatment of pain: cognitive-behavioral therapy, or CBT. CBT isn’t as new and exciting as some experimental approaches that Dr. Borckardt is working with and studying, such as transcranial magnetic stimulation and transcranial direct current stimulation. But CBT is readily available and typically covered by insurance (unlike those experimental therapies), and has been shown in numerous studies to be highly effective, he said.
CBT and ‘360’ programs
CBT also was mentioned by Dr. Volkow in her June 2016 blog post. She called it “one of the most effective pain treatments,” and said that “assisting patients in learning to change their pain-related thoughts, emotions, and behaviors is going to help with their condition, regardless of other pharmacological interventions.”
Dr. Borckardt said it is particularly effective in the context of programs that provide what he called “a 360 approach.” These multifaceted treatment programs aim to help chronic pain patients taper off of opioid medications and to find other approaches to managing pain.
Only a handful of such comprehensive, intensive outpatient programs exist across the United States, but the concept is taking hold, driven in part by the opioid crisis, and more centers are opening. In fact, Dr. Borckardt is helping to develop such a program at MUSC. The program will likely be housed in the MUSC Wellness Center, and much like the Mayo Clinic’s Pain Rehabilitation Center, which opened in 1974 and was one of the first such programs in the world, the MUSC program will involve an integrated team of health care professionals that provide CBT for pain, physical therapy, occupational therapy, and other programs designed to help patients living with pain.
This is widely accepted as being the best approach for pain rehabilitation, Dr. Borckardt said.
TMS and TDCS
Dr. Borckardt also has worked with some more cutting-edge approaches to pain management. Transcranial magnetic stimulation (TMS), which is approved for the treatment of depression, also has shown promise for treating pain. TMS can target areas in the brain involved with specific functioning, such as emotional regulation. The high-frequency stimulation is believed to enhance that particular area and produce a clinical effect.
“Pain is a subjective, largely psychological experience, and it involves an emotional component,” he said, explaining that the rationale for the use of TMS for pain is that the emotional component of the pain experience can be targeted along with the sensory and cognitive aspects of the pain experience.
TMS is being used in various studies, and has been used off label for pain management, but the out-of-pocket cost is high because it is not currently approved for pain and is therefore not covered by insurance, he said.
For depression, TMS typically is used 5 days per week for 3 weeks – at a cost ranging anywhere from $100 to $500 per session. It remains unclear how many sessions would be required for pain treatment to produce a sustained effect, but it would likely be similar to the requirements for depression treatment, and may also require follow-up treatments, Dr. Borckardt said.
“We do know with reasonable confidence that it impacts pain perception and can impact sensory or emotional components of pain, depending on the part of the brain treated. But we don’t know how long we have to treat, how often, or how durable the effects are,” he said, noting that several groups are studying TMS for pain.
Notably, there is also some very preliminary evidence that TMS may be useful for treating addiction by affecting cravings for substances such as opiates, nicotine, and alcohol. If that effect is confirmed, TMS could help chronic pain patients reduce their need for higher opioid doses, thereby lowering the risk of overdose, which is an important factor in the opioid crisis; most patients who use opioids don’t become addicted, but they can be at risk for overdose because of the need for high doses to control their pain, he explained.
In one study, the use of TMS postoperatively reduced the amount of in-hospital drug use by 40%, he said, noting that the reduction could convert to a reduction in the use of pain medication after discharge as well.
A related treatment, transcranial direct current stimulation, or tDCS, involves placement of electrodes directly on the scalp to run weak electrical currents through the brain, again trying to alter areas associated with pain perception. Ongoing studies are looking at combining tDCS and CBT with the hope that the two will have synergistic effects, including one in veterans with low back pain and opioid misuse. Another small pilot study in patients with fibromyalgia recently concluded and had some promising results.
These and other nonpharmacologic approaches to pain management could play an important role in the effort to reduce opioid prescribing. Currently, about 90 Americans die each day after overdosing on opioids, according to NIDA, and the CDC estimates that prescription opioid misuse alone in the United States costs $78.5 billion per year in health care, lost productivity, addiction treatment, and criminal justice involvement.
In her plea to psychiatrists to take action to intervene, Dr. Volkow underscored the value that they bring to the table.
“It is crucial that we not lose sight of the reality and complexity of chronic pain as management of chronic noncancer pain moves toward greater caution around opioid medication. This should not be solely an issue for primary care medicine or neurology, but also for specialties such as psychiatry that have much to offer people who are suffering from complex disorders in which physical symptoms merge with psychological distress,” she wrote.
Dr. Volkow has written hundreds of peer-reviewed articles, including analyses of the opioid crisis (N Engl J Med. 2017 Jul 27;377[4]:391-4) and (Neuron. 2016 Oct 19[2]:294-7). Dr. Spiegel is coauthor of Trance and Treatment: Clinical Uses of Hypnosis (Washington: American Psychiatric Association Publishing, 2004), a textbook written to help psychiatrists and other physicians learn to use hypnosis. Dr. Borckardt receives research funding from the National Institutes of Health.
Studies backing certain FDA approvals found lacking
, two studies showed.
Between 2009 and 2013, the FDA granted accelerated approval for 22 drugs with 24 indications, which were supported by 30 preapproval studies with a median of 132 subjects. Only 12 of those studies (40%) were randomized, and only 6 (20%) were double blind. Eight (27%) included fewer than 100 subjects, and 20 (67%) included fewer than 200, reported Huseyin Naci, PhD, of the London School of Economics and Political Science, and his colleagues.
Further, at a minimum of 3 years after the approval, only half of the 38 confirmatory studies required by the FDA were completed, and, ultimately, only 25 of the 48 (66%) examined clinical efficacy, only 7 (18%) evaluated longer follow-up, and only 6 (16%) focused on safety, the investigators reported (JAMA. 2017 Aug 15;318[7]:626-36).
The proportion of studies that were randomized was slightly, but not significantly greater in the postapproval vs. preapproval period (56% vs. 40%), and only one was double blind. For 10 of 24 indications (42%), postapproval study requirements were completed and demonstrated efficacy based on surrogate measures, the investigators said.
Of the 14 remaining indications (58%) for which FDA study requirements had not yet been met, 2 (8%) had at least one confirmatory study that failed to demonstrate clinical benefit (without apparent action on the part of the FDA to rescind approval or impose additional requirements), 2 (8%) had a least one confirmatory study that was terminated, and 3 (13%) had at least one confirmatory study that was delayed by more than a year. The required studies for the remaining indications were progressing as planned, but for eight indications, clinical benefit had not yet been confirmed at 5 or more years after approval.
Similar concerns were seen in a review of clinical studies used to support high-risk medical device modification approvals. Such devices often undergo numerous modifications that receive FDA approval through one of six premarket approval (PMA) supplement pathways, and a total of 83 studies that supported 78 panel-track supplements (one of the 6 pathways and the only one that always required clinical data) approved between April 19, 2006, and Oct. 9, 2015, were identified. Nearly all (98%) of those 78 modifications were supported by just one study; only 45% of those studies were randomized clinical trials, and only 30% were blinded, reported Sarah Y. Zheng, MD, of the University of California, San Francisco, and her colleagues (JAMA. 2017 Aug 15;318[7]:619-25).
The median number of patients in the studies was 185, and the median follow-up was 180 days. Further, of 150 primary endpoints in the studies, 121 (81%) were surrogate endpoints, 57 (38%) were compared with controls, and 6 (11%) of those involved retrospective rather than active controls.
Age and sex were not reported for all enrolled patients in 40% and 30% of the studies, respectively, and in the case of one device modification study, 91% of enrolled patients were not included in the primary analysis.
“Given the extensive modification of many PMA supplement devices and the median preapproval follow-up of 6 months, obtaining additional data via [postapproval studies] is critical. However, the FDA required [postapproval studies] for the minority (37%) of the panel-track supplements,” the investigators noted, adding that only 13% of initiated postapproval studies were completed between 3 and 5 years after FDA approval, and that no warning letters, penalties, or fines were administered for noncompliance.
“These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved,” they concluded.
Dr. Zheng and her colleagues reported having no conflicts of interest. Dr. Naci reported having no conflicts of interest. One coauthor, Aaron S. Kesselheim, MD, reported receiving unrelated grants from the FDA Office of Generic Drugs and Division of Health Communication.
The findings by Naci and colleagues and Zheng and colleagues raise concerns about whether the current regulatory system is too permissive in not requiring traditional randomized controlled trials for postmarketing evaluation of drugs that receive accelerated approval, and for high-risk medical device supplemental design modifications, Robert Califf, MD, wrote in an editorial.
However, randomization and blinding are not always feasible, and “despite the concerns raised by these two articles … it is important to remember that decisions about postmarket requirements and monitoring of these studies are overseen by full-time FDA employees with no financial conflicts,” he said, adding that “this underscores the importance of a talented workforce at the FDA with the variety of skills needed to assimilate information about manufacturing, quality systems, clinical outcomes, and the well-being and preferences of patients.”
A sweeping overhaul of the overall system is also needed, and is underway, he said, noting that substantial progress in balancing safety with access to effective therapies will come from systemic changes in the ecosystem rather than from imposing more severe demands on individual products (JAMA. 2017 Aug 15;318[7]:614-6).
Indeed, it is time to seriously consider how increasingly robust data and analytic capabilities and more efficient prospective research systems can be used to address the concerns raised in these articles, he said, adding that “as technological improvements and … connected networks of health systems make it feasible to conduct high-quality, low-cost RCTs [randomized, controlled trials] and to continuously monitor product performance, the impediments to progress are mostly those built into the culture of medicine and health care.”
Dr. Califf is with Duke Health and Duke University, Durham, N.C. He was the Commissioner of Food and Drugs, Food and Drug Administration, from February 2016 to January 2017. He currently receives consulting payments from Merck and is employed as a scientific adviser by Verily Life Sciences (Alphabet).
The findings by Naci and colleagues and Zheng and colleagues raise concerns about whether the current regulatory system is too permissive in not requiring traditional randomized controlled trials for postmarketing evaluation of drugs that receive accelerated approval, and for high-risk medical device supplemental design modifications, Robert Califf, MD, wrote in an editorial.
However, randomization and blinding are not always feasible, and “despite the concerns raised by these two articles … it is important to remember that decisions about postmarket requirements and monitoring of these studies are overseen by full-time FDA employees with no financial conflicts,” he said, adding that “this underscores the importance of a talented workforce at the FDA with the variety of skills needed to assimilate information about manufacturing, quality systems, clinical outcomes, and the well-being and preferences of patients.”
A sweeping overhaul of the overall system is also needed, and is underway, he said, noting that substantial progress in balancing safety with access to effective therapies will come from systemic changes in the ecosystem rather than from imposing more severe demands on individual products (JAMA. 2017 Aug 15;318[7]:614-6).
Indeed, it is time to seriously consider how increasingly robust data and analytic capabilities and more efficient prospective research systems can be used to address the concerns raised in these articles, he said, adding that “as technological improvements and … connected networks of health systems make it feasible to conduct high-quality, low-cost RCTs [randomized, controlled trials] and to continuously monitor product performance, the impediments to progress are mostly those built into the culture of medicine and health care.”
Dr. Califf is with Duke Health and Duke University, Durham, N.C. He was the Commissioner of Food and Drugs, Food and Drug Administration, from February 2016 to January 2017. He currently receives consulting payments from Merck and is employed as a scientific adviser by Verily Life Sciences (Alphabet).
The findings by Naci and colleagues and Zheng and colleagues raise concerns about whether the current regulatory system is too permissive in not requiring traditional randomized controlled trials for postmarketing evaluation of drugs that receive accelerated approval, and for high-risk medical device supplemental design modifications, Robert Califf, MD, wrote in an editorial.
However, randomization and blinding are not always feasible, and “despite the concerns raised by these two articles … it is important to remember that decisions about postmarket requirements and monitoring of these studies are overseen by full-time FDA employees with no financial conflicts,” he said, adding that “this underscores the importance of a talented workforce at the FDA with the variety of skills needed to assimilate information about manufacturing, quality systems, clinical outcomes, and the well-being and preferences of patients.”
A sweeping overhaul of the overall system is also needed, and is underway, he said, noting that substantial progress in balancing safety with access to effective therapies will come from systemic changes in the ecosystem rather than from imposing more severe demands on individual products (JAMA. 2017 Aug 15;318[7]:614-6).
Indeed, it is time to seriously consider how increasingly robust data and analytic capabilities and more efficient prospective research systems can be used to address the concerns raised in these articles, he said, adding that “as technological improvements and … connected networks of health systems make it feasible to conduct high-quality, low-cost RCTs [randomized, controlled trials] and to continuously monitor product performance, the impediments to progress are mostly those built into the culture of medicine and health care.”
Dr. Califf is with Duke Health and Duke University, Durham, N.C. He was the Commissioner of Food and Drugs, Food and Drug Administration, from February 2016 to January 2017. He currently receives consulting payments from Merck and is employed as a scientific adviser by Verily Life Sciences (Alphabet).
, two studies showed.
Between 2009 and 2013, the FDA granted accelerated approval for 22 drugs with 24 indications, which were supported by 30 preapproval studies with a median of 132 subjects. Only 12 of those studies (40%) were randomized, and only 6 (20%) were double blind. Eight (27%) included fewer than 100 subjects, and 20 (67%) included fewer than 200, reported Huseyin Naci, PhD, of the London School of Economics and Political Science, and his colleagues.
Further, at a minimum of 3 years after the approval, only half of the 38 confirmatory studies required by the FDA were completed, and, ultimately, only 25 of the 48 (66%) examined clinical efficacy, only 7 (18%) evaluated longer follow-up, and only 6 (16%) focused on safety, the investigators reported (JAMA. 2017 Aug 15;318[7]:626-36).
The proportion of studies that were randomized was slightly, but not significantly greater in the postapproval vs. preapproval period (56% vs. 40%), and only one was double blind. For 10 of 24 indications (42%), postapproval study requirements were completed and demonstrated efficacy based on surrogate measures, the investigators said.
Of the 14 remaining indications (58%) for which FDA study requirements had not yet been met, 2 (8%) had at least one confirmatory study that failed to demonstrate clinical benefit (without apparent action on the part of the FDA to rescind approval or impose additional requirements), 2 (8%) had a least one confirmatory study that was terminated, and 3 (13%) had at least one confirmatory study that was delayed by more than a year. The required studies for the remaining indications were progressing as planned, but for eight indications, clinical benefit had not yet been confirmed at 5 or more years after approval.
Similar concerns were seen in a review of clinical studies used to support high-risk medical device modification approvals. Such devices often undergo numerous modifications that receive FDA approval through one of six premarket approval (PMA) supplement pathways, and a total of 83 studies that supported 78 panel-track supplements (one of the 6 pathways and the only one that always required clinical data) approved between April 19, 2006, and Oct. 9, 2015, were identified. Nearly all (98%) of those 78 modifications were supported by just one study; only 45% of those studies were randomized clinical trials, and only 30% were blinded, reported Sarah Y. Zheng, MD, of the University of California, San Francisco, and her colleagues (JAMA. 2017 Aug 15;318[7]:619-25).
The median number of patients in the studies was 185, and the median follow-up was 180 days. Further, of 150 primary endpoints in the studies, 121 (81%) were surrogate endpoints, 57 (38%) were compared with controls, and 6 (11%) of those involved retrospective rather than active controls.
Age and sex were not reported for all enrolled patients in 40% and 30% of the studies, respectively, and in the case of one device modification study, 91% of enrolled patients were not included in the primary analysis.
“Given the extensive modification of many PMA supplement devices and the median preapproval follow-up of 6 months, obtaining additional data via [postapproval studies] is critical. However, the FDA required [postapproval studies] for the minority (37%) of the panel-track supplements,” the investigators noted, adding that only 13% of initiated postapproval studies were completed between 3 and 5 years after FDA approval, and that no warning letters, penalties, or fines were administered for noncompliance.
“These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved,” they concluded.
Dr. Zheng and her colleagues reported having no conflicts of interest. Dr. Naci reported having no conflicts of interest. One coauthor, Aaron S. Kesselheim, MD, reported receiving unrelated grants from the FDA Office of Generic Drugs and Division of Health Communication.
, two studies showed.
Between 2009 and 2013, the FDA granted accelerated approval for 22 drugs with 24 indications, which were supported by 30 preapproval studies with a median of 132 subjects. Only 12 of those studies (40%) were randomized, and only 6 (20%) were double blind. Eight (27%) included fewer than 100 subjects, and 20 (67%) included fewer than 200, reported Huseyin Naci, PhD, of the London School of Economics and Political Science, and his colleagues.
Further, at a minimum of 3 years after the approval, only half of the 38 confirmatory studies required by the FDA were completed, and, ultimately, only 25 of the 48 (66%) examined clinical efficacy, only 7 (18%) evaluated longer follow-up, and only 6 (16%) focused on safety, the investigators reported (JAMA. 2017 Aug 15;318[7]:626-36).
The proportion of studies that were randomized was slightly, but not significantly greater in the postapproval vs. preapproval period (56% vs. 40%), and only one was double blind. For 10 of 24 indications (42%), postapproval study requirements were completed and demonstrated efficacy based on surrogate measures, the investigators said.
Of the 14 remaining indications (58%) for which FDA study requirements had not yet been met, 2 (8%) had at least one confirmatory study that failed to demonstrate clinical benefit (without apparent action on the part of the FDA to rescind approval or impose additional requirements), 2 (8%) had a least one confirmatory study that was terminated, and 3 (13%) had at least one confirmatory study that was delayed by more than a year. The required studies for the remaining indications were progressing as planned, but for eight indications, clinical benefit had not yet been confirmed at 5 or more years after approval.
Similar concerns were seen in a review of clinical studies used to support high-risk medical device modification approvals. Such devices often undergo numerous modifications that receive FDA approval through one of six premarket approval (PMA) supplement pathways, and a total of 83 studies that supported 78 panel-track supplements (one of the 6 pathways and the only one that always required clinical data) approved between April 19, 2006, and Oct. 9, 2015, were identified. Nearly all (98%) of those 78 modifications were supported by just one study; only 45% of those studies were randomized clinical trials, and only 30% were blinded, reported Sarah Y. Zheng, MD, of the University of California, San Francisco, and her colleagues (JAMA. 2017 Aug 15;318[7]:619-25).
The median number of patients in the studies was 185, and the median follow-up was 180 days. Further, of 150 primary endpoints in the studies, 121 (81%) were surrogate endpoints, 57 (38%) were compared with controls, and 6 (11%) of those involved retrospective rather than active controls.
Age and sex were not reported for all enrolled patients in 40% and 30% of the studies, respectively, and in the case of one device modification study, 91% of enrolled patients were not included in the primary analysis.
“Given the extensive modification of many PMA supplement devices and the median preapproval follow-up of 6 months, obtaining additional data via [postapproval studies] is critical. However, the FDA required [postapproval studies] for the minority (37%) of the panel-track supplements,” the investigators noted, adding that only 13% of initiated postapproval studies were completed between 3 and 5 years after FDA approval, and that no warning letters, penalties, or fines were administered for noncompliance.
“These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved,” they concluded.
Dr. Zheng and her colleagues reported having no conflicts of interest. Dr. Naci reported having no conflicts of interest. One coauthor, Aaron S. Kesselheim, MD, reported receiving unrelated grants from the FDA Office of Generic Drugs and Division of Health Communication.
FROM JAMA
Key clinical point:
Major finding: For 8 of 24 drug indications, clinical benefit had not yet been confirmed at 5 or more years after approval, and only 13% of initiated postapproval studies were completed between 3 and 5 years after FDA device supplement approvals.
Data source: A review of FDA documents regarding 22 drugs with 24 indications, and a descriptive study of 83 clinical studies supporting 78 panel-track supplements.
Disclosures: Dr. Zheng and her colleagues reported having no conflicts of interest. Dr. Naci reported having no conflicts of interest. One coauthor, Aaron S. Kesselheim, MD, reported receiving unrelated grants from the FDA Office of Generic Drugs and Division of Health Communication.
ALLOZITHRO trial: HSCT patients fared worse with azithromycin
Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.
The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.
Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).
A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.
Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.
The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.
The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.
Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).
A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.
Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.
The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
Administration of azithromycin beginning at the time of conditioning in patients undergoing allogeneic hematopoietic stem cell transplant resulted in worse airflow decline–free survival than did placebo, according to findings from the randomized ALLOZITHRO trial.
The 2-year airflow decline–free survival rate was 32.8% in 243 patients who received 250 mg of azithromycin for 2 years, compared with 41.3% in 237 who received placebo (hazard ratio, 1.3), Anne Bergeron, MD, of Hopital Saint-Louis, Paris, and her colleagues reported in the Aug. 8 issue of JAMA.
Further, of 22 patients who experienced bronchiolitis obliterans syndrome, 15 were in the azithromycin group, compared with 7 in the placebo group, and 2-year mortality was increased in the azithromycin group (56.6% vs. 70.1%; hazard ratio, 1.5) the investigators noted (JAMA. 2017 Aug 8;318[6]:557-66. doi: 10.1001/jama.2017.9938).
A post hoc analysis showed that the 2-year cumulative incidence of hematological relapse was 33.5% with azithromycin vs. 22.3% with placebo; the trial was terminated early because of this unexpected finding.
Although prior studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome, which has been shown to increase morbidity and mortality after allogeneic HSCT, the findings of this parallel-group trial conducted in 19 French transplant centers between February 2014 and August 2015 showed a decrease in survival and an increase in hematological relapse at 2 years with azithromycin vs. placebo. The findings, however, are limited by several factors – including the trial’s early termination – and require further study, particularly of the potential for harm related to relapse, the investigators concluded.
The ALLOZITHRO trial (NCT01959100) was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.
FROM JAMA
Key clinical point:
Major finding: The 2-year airflow decline–free survival rates were 32.8% and 41.3% in the azithromycin and placebo groups, respectively (hazard ratio, 1.3).
Data source: The randomized, placebo-controlled ALLOZITHRO trial of 480 patients.
Disclosures: The ALLOZITHRO trial was funded by the French Cancer Institute, Oxygene, and SFGM-TC Capucine. Dr. Bergeron reported receiving unrestricted research grant funding for the trial from the French Ministry of Health, SFGM-TC Capucine association, and SOS Oxygene; receiving speaker fees from Merck, Gilead, and Pfizer; and serving on the advisory board of Merck.