The Food and Drug Administration has eliminated the boxed warning for risk of asthma-related death from the labels of products containing both an inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA), the agency announced.

In 2011, the FDA required companies manufacturing fixed-dose LABA-ICS combination products to conduct 26-week clinical safety trials to evaluate the risks of serious adverse asthma-related events in patients treated with these drugs. Specifically, the companies had to compare the risks of taking a LABA in combination with an ICS with the risks of taking an ICS alone.

Wikimedia Commons/FitzColinGerald/Creative Commons License

“These trials showed that LABAs, when used with ICS, did not significantly increase the risk of asthma-related hospitalizations, the need to insert a breathing tube known as intubation, or asthma-related deaths, compared to ICS alone,” the FDA said in the statement.

The trials also demonstrated that using the combination reduced asthma exacerbations, compared with using ICS alone, and that most of the exacerbations “were those that required at least 3 days of systemic corticosteroids” – information that is being added the product labels, according to the FDA.

The products that will no longer carry this boxed warning in their labels include AstraZeneca’s budesonide/formoterol fumarate dihydrate (Symbicort) and GlaxoSmithKline’s fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone propionate/salmeterol (Advair Diskus and Advair HFA).

The FDA also approved updates to the Warnings and Precautions section of labeling for the ICS/LABA class, which now includes a description of the four trials. Information on the efficacy of the drugs, found in the trials, has been added to the Clinical Studies section of the labels as well.

In a related safety announcement, the FDA stated the following: “Using LABAs alone to treat asthma without an ICS to treat lung inflammation is associated with an increased risk of asthma-related death. Therefore, the Boxed Warning stating this will remain in the labels of all single-ingredient LABA medicines, which are approved to treat asthma, chronic obstructive pulmonary disease (COPD), and wheezing caused by exercise. The labels of medicines that contain both an ICS and LABA also retain a Warning and Precaution related to the increased risk of asthma-related death when LABAs are used without an ICS to treat asthma.


 

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The Food and Drug Administration has eliminated the boxed warning for risk of asthma-related death from the labels of products containing both an inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA), the agency announced.

In 2011, the FDA required companies manufacturing fixed-dose LABA-ICS combination products to conduct 26-week clinical safety trials to evaluate the risks of serious adverse asthma-related events in patients treated with these drugs. Specifically, the companies had to compare the risks of taking a LABA in combination with an ICS with the risks of taking an ICS alone.

Wikimedia Commons/FitzColinGerald/Creative Commons License

“These trials showed that LABAs, when used with ICS, did not significantly increase the risk of asthma-related hospitalizations, the need to insert a breathing tube known as intubation, or asthma-related deaths, compared to ICS alone,” the FDA said in the statement.

The trials also demonstrated that using the combination reduced asthma exacerbations, compared with using ICS alone, and that most of the exacerbations “were those that required at least 3 days of systemic corticosteroids” – information that is being added the product labels, according to the FDA.

The products that will no longer carry this boxed warning in their labels include AstraZeneca’s budesonide/formoterol fumarate dihydrate (Symbicort) and GlaxoSmithKline’s fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone propionate/salmeterol (Advair Diskus and Advair HFA).

The FDA also approved updates to the Warnings and Precautions section of labeling for the ICS/LABA class, which now includes a description of the four trials. Information on the efficacy of the drugs, found in the trials, has been added to the Clinical Studies section of the labels as well.

In a related safety announcement, the FDA stated the following: “Using LABAs alone to treat asthma without an ICS to treat lung inflammation is associated with an increased risk of asthma-related death. Therefore, the Boxed Warning stating this will remain in the labels of all single-ingredient LABA medicines, which are approved to treat asthma, chronic obstructive pulmonary disease (COPD), and wheezing caused by exercise. The labels of medicines that contain both an ICS and LABA also retain a Warning and Precaution related to the increased risk of asthma-related death when LABAs are used without an ICS to treat asthma.


 

[email protected]

The Food and Drug Administration has eliminated the boxed warning for risk of asthma-related death from the labels of products containing both an inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA), the agency announced.

In 2011, the FDA required companies manufacturing fixed-dose LABA-ICS combination products to conduct 26-week clinical safety trials to evaluate the risks of serious adverse asthma-related events in patients treated with these drugs. Specifically, the companies had to compare the risks of taking a LABA in combination with an ICS with the risks of taking an ICS alone.

Wikimedia Commons/FitzColinGerald/Creative Commons License

“These trials showed that LABAs, when used with ICS, did not significantly increase the risk of asthma-related hospitalizations, the need to insert a breathing tube known as intubation, or asthma-related deaths, compared to ICS alone,” the FDA said in the statement.

The trials also demonstrated that using the combination reduced asthma exacerbations, compared with using ICS alone, and that most of the exacerbations “were those that required at least 3 days of systemic corticosteroids” – information that is being added the product labels, according to the FDA.

The products that will no longer carry this boxed warning in their labels include AstraZeneca’s budesonide/formoterol fumarate dihydrate (Symbicort) and GlaxoSmithKline’s fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone propionate/salmeterol (Advair Diskus and Advair HFA).

The FDA also approved updates to the Warnings and Precautions section of labeling for the ICS/LABA class, which now includes a description of the four trials. Information on the efficacy of the drugs, found in the trials, has been added to the Clinical Studies section of the labels as well.

In a related safety announcement, the FDA stated the following: “Using LABAs alone to treat asthma without an ICS to treat lung inflammation is associated with an increased risk of asthma-related death. Therefore, the Boxed Warning stating this will remain in the labels of all single-ingredient LABA medicines, which are approved to treat asthma, chronic obstructive pulmonary disease (COPD), and wheezing caused by exercise. The labels of medicines that contain both an ICS and LABA also retain a Warning and Precaution related to the increased risk of asthma-related death when LABAs are used without an ICS to treat asthma.


 

[email protected]

Traumatic brain injury (TBI) is a health concern for the U.S. Military Health System (MHS) as well as the VHA. It occurs in both deployed and nondeployed settings; however, Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) and improved reporting mechanisms have dramatically increased TBI diagnoses in active-duty service members. According to the Defense and Veterans Brain Injury Center (DVBIC), more than 370,000 service members have been diagnosed with a TBI since 2000 (Figure).¹

Background

The DoD and the VA are collaborating on clinical research studies to identify, understand, and treat the long-term effects of TBI that can affect patients and their families. Most TBIs are mild (mTBIs), also called concussions, and patients typically recover within a few weeks (Table 1). However, some individuals with mTBI experience symptoms that may persist for months or years. A meta-analysis by Perry and colleagues showed that the prevalence or risk of a neurologic disorder, depression, or other mental health issue following mTBI was 67% higher compared with that in uninjured controls.²

Patients with any severity of TBI may require assistance with activities of daily living (ADLs), such as bathing, dressing, managing medications, and feeding. Patients also may need help with instrumental ADLs, such as meal preparation, grocery shopping, household chores, child care, getting to appointments or activities, coordination of educational and vocational services, financial and benefits management, and supportive listening.

Increased injuries have spurred the DoD and VA to coordinate health care to provide a seamless transition for patients between the 2 agencies. However, individuals who sustained a TBI may need various levels of caregiver assistance over time.

TBI and Caregivers

Despite better agency coordination for patients, caregivers can experience stress. Griffin and colleagues found that caregiving responsibilities can compete with other demands on the caregiver, such as work and family, and may negatively impact their health and finances.^3,4

Lou and colleagues studied the factors associated with caring for chronically ill family members that may result in stress for the caregivers.⁵ Along with an unaccounted for economic contribution, caregivers may face lost work time and pay and limitations on work travel and work advancement. Additionally, lost time for leisure, travel, social activities, family obligations, and retirement could result in physical and mental drain on the caregiver. Stress may reach a level at which the caregivers risk psychological distress. The study also noted that families with perceived high stress experience disrupted family functioning. Some TBI caregiver studies sought to understand how best to evaluate and determine the level of caregiver burden, and other studies investigated appropriate interventions.^6-9

Health care practitioners within the federal health care system may benefit from a greater awareness of caregiver needs and caregiver resources. Caregiver support can improve outcomes for both the caregiver and care recipient, and many organizations and resources already exist to assist the caregiver. This article reviews recent published literature on TBI caregivers of patients with TBI across civilian, military, and veteran populations and lists caregiver resources for additional information, assistance, and support.

Literature Review

The DVBIC defines the term caregiver as “any family or support person(s) relied upon by the service member or veteran with traumatic brain injury (TBI) who assumes primary responsibility for ensuring the needed level of care and overall well-being of that service member or veteran. A family or family caregiver may include spouse, parents, children, other extended family members, as well as significant others and friends.”³

In the following discussion, findings from military and veteran literature are separated from civilian population findings to highlight similarities and differences between these 2 bodies of research. Several of the studies in the military/veteran cohorts include polytrauma patients with comorbid physical and mental health issues not necessarily found in civilian literature.

Civilian Literature

A 2015 systematic review by Anderson and colleagues on coping and psychological adjustment in TBI caregivers indicated no Class I or Class II studies.¹⁰ Four Class III and 3 Class IV studies were found. The authors suggest that more rigorous studies (ie, Class I and II) are needed.

Despite these limitations, peer-reviewed literature indicates that the levels of stress and distress in TBI caregivers are consistent with reports for other diseases. In a civilian population, Carlozzi and colleagues found that TBI caregivers who reported stress, distress, anxiety, and feeling overwhelmed often had concerns for their social, emotional, physical, cognitive health, as well as feelings of loss.⁵ In addition, caregivers may need to take leaves of absence or leave the workforce entirely to provide for a family member or friend who had a TBI—often leading to financial strain (eg, depleting assets, accumulating debt). These challenges may occur during prime earning years, and the caregiver may lose the ability to resume work if the care receiver requires care for extended periods.¹¹

Kratz and colleagues showed that caregivers of individuals with moderate-to-severe TBI: (1) felt overburdened with responsibilities; (2) lacked personal time and time for self-care; (3) felt their lives were interrupted or lost; (4) grieved the loss of the person with TBI; and (5) endorsed anger, guilt, anxiety, and sadness.¹²

Perceptions differed between caregiver parents and caregiver partners. Parents expressed feelings of grief and sadness related to the “loss of the person before the TBI.” Parents also reported a sense of guilt and responsibility for their child’s TBI and feelings of being tied down to the individual with TBI. Parents experienced a greater level of stress if the son or daughter with TBI still lived at home. Partners expressed frustration and despair related to their role as sole decision maker and care provider. Partners’ distress also related to the partner relationship and the relationship between children and the individual with TBI.

Verhasghe and colleagues found that partners experience a greater degree of stress than do parents.¹³ Young families with minimal social support for coping with financial, psychiatric, and medical problems were the most vulnerable to stress. A systematic review by Ennis and colleagues evaluated depression and anxiety in caregiver parents vs spouses.¹⁴ Although methods and quality differed in the studies, findings indicated high levels of distress regardless of the type of caregiver.

Anderson and colleagues used the Ways of Coping Questionnaire to evaluate the association between coping and psychological adjustment in caregivers of TBI individuals.¹⁰ The use of emotion-focused coping and problem solving was possibly associated with psychological adjustment in caregivers. Verhasghe and colleagues indicated that the nature of the injuries more than the severity of TBI determined the level of stress up to 15 years after the TBI.¹³ Gender and social and professional support also influenced coping. The review identified the need to develop models of long-term support and care.

An Australian cohort of 79 family caregivers participated in a study by Perlesz and colleagues.¹⁵ Participants’ caregiving responsibilities averaged 19.3 months posttrauma. The Family Satisfaction Scale, Beck Depression Inventory, State Anxiety Inventory, and Profile of Mood States were used in this analysis. Male caregivers reported distress in terms of anger and fatigue; female caregivers were at greatest risk of poor psychosocial outcomes. Although findings from primary caregivers indicated that 35% to 49% displayed enough distress to warrant clinical intervention, between 51% and 80% were not psychologically distressed and were satisfied with their families. Data supported previous reports suggesting caregivers are “not universally distressed.”¹⁵

Manskow and colleagues followed patients with severe TBI and assessed caregiver burden 1 year later. Using the Caregiver Burden Scale, caregivers reported the highest scores (N = 92) on the General Strain Index followed by the Disappointment Index.¹⁶ Bayen and colleagues also studied caregivers of severe TBI patients.¹⁷ Objective and subjective caregiver burden data 4 years later indicated 44% of caregivers (N = 98) reported multidimensional burden. Greater burden was associated in caring for individuals who had poorer Glasgow Outcome Scale Extended scores and more severe cognitive disorders.

Military and Veteran Literature

Griffin and colleagues conducted the Family and Caregiver Experience Study (FACES) with caregivers (N = 564) of service members who incurred a TBI.³ According to the caregivers, two-thirds of the patients lost consciousness for more than 30 minutes, which was followed by inpatient rehabilitation care at a VA polytrauma center between 2001 and 2009. The majority of caregivers of TBI patients were female (79%) and aged < 60 years (84%). Parents comprised 62% and spouses 32% of the cohort. Caregivers tended to have some level of education beyond high school (73%), were married (77%), either worked or were enrolled in school (55%), and earned less than $40,000 a year (70%). Common characteristics of the care receivers were male gender (95%), average age 30, high school educated (52%), married (almost 50%), and employed (50%). Forty-five percent of the care receivers were injured 4 to 6 years prior, and 12% were injured 7 or more years prior. The study determined the caregivers’ perception of intensity of care needed and indicated that families as well as clinicians need to plan for some level of long-term support and services.

In addition to the TBI-related caregiving needs, Griffin and colleagues found in a military population that other medical conditions impacted the level of caregiving and strained a marriage.¹⁸ Their study found that in a military population between 30% and 50% of marriages of patients with TBI dissolved within the first 10 years after injury. Caregivers may need to learn nursing activities, such as tube feedings, tracheostomy and stoma care, catheter care, wound care, and medication administration. Family stress with caregiving may interfere with the ability to understand information related to the care receivers’ medical care and may require multiple formats to explain care needs. Sander and colleagues associated better emotional functioning in caregivers with greater social integration and occupation outcomes in patients at the postacute rehabilitation program phase (within 6 months of injury).¹⁹ However, these outcomes did not continue more than 6 months postinjury.

Intervention and Research Studies

Powell and colleagues used a telephone-based, individualized TBI education intervention along with problem-solving mentoring (10 phone calls at 2-week intervals following patient discharge for moderate-to-severe TBI from a level 1 trauma center) to determine which programs, activities, and coping strategies could decrease caregiver challenges.²⁰ The telephone interventions resulted in better caregiver outcomes than usual care as measured by composite scores on the Bakas Caregiving Outcomes Scale (BCOS) and the Brief Symptom Inventory (BSI-18) at 6 months post-TBI survivor discharge. Dyer and colleagues explored Internet approaches and mobile applications to provide support for caregivers. ¹⁸ In a small sample of 10 caregivers, Damianakis and colleagues conducted a 10-session pilot videoconferencing support-group intervention program led by a clinician. Results indicated that the intervention enhanced caregiver coping and problem-solving skills.⁷

Petranovich and colleagues examined the efficacy of counselor-assisted problem-solving interventions in improving long-term caregiver psychological functioning following TBI in adolescents.²¹ Their findings support the utility of online interventions in improving long-term caregiver psychological distress, particularly for lower income families. Although this study focused on adolescents, research may indicate merit in an adult population. In relatives of patients with severe TBI, Norup and colleagues associated improvements in health-related quality of life (HRQOL) with improvements in symptoms of anxiety and depression without specific intervention.²²

Moriarty and colleagues conducted a randomized controlled trial for veterans who received care at a VA polytrauma center and their family members who participated in a veteran’s in-home program (VIP) intervention.⁹ The study aimed to evaluate how VIP affected family members’ caregiver burden, depressive symptoms, satisfaction with caregiving, and the program’s acceptability. Eighty-one veterans with a key family member were randomized. Of those, 63 veterans completed a follow-up interview. The intervention consisted of 6 home visits of 1 to 2 hours each and 2 telephone calls from an occupational therapist over 3 to 4 months. Family members were invited to participate during the home visits. The control group received usual clinic care with 2 telephone calls during the study period. All participants received the follow-up interview 3 to 4 months after baseline interviews. The severity of TBI was determined by a review of the electronic medical record using the VA/DoD Clinical Practice Guidelines. Findings of this study indicated that family members in the intervention group showed significantly lower depressive symptom scores and caregiver burden scores.⁹ Additionally, the veterans in the intervention group exhibited higher community integration and ability to manage their targeted outcomes. Further research may indicate that VIP could assist patients with TBI and caregivers in an active-duty population.

The DVBIC is the executive agent for a congressionally mandated 15-year longitudinal study on TBI incurred by members of the armed services in OEF and OIF. The John Warner National Defense Authorization Act for Fiscal Year 2007 outlined the study. An initial finding identified the need for an HRQOL outcomes assessment specific to TBI caregivers.²³ Having these data will allow investigators to fully determine the comprehensive impact of caring for a person who sustained a mild, moderate, severe, or penetrating TBI and to evaluate the effectiveness of interventions designed to address caregivers’ needs. To date, the study has identified the following HRQOL themes generated among caregivers: social health, emotional health, physical/medical health, cognitive functioning, and feelings of loss (related to changing social roles). Carlozzi and colleagues noted that the study also aimed to identify a sensitive outcome measure to evaluate quality of life in the caregivers over time.⁷

Knowledge Gaps

Ongoing studies focus on caregiving for individuals with various illnesses and needs. Some of the information in each study may be beneficial to TBI caregivers who are not fully aware of resources and interventions. For example, Fortune and colleagues, Hirano and colleagues, and Grover and colleagues are studying caregiver activities involving other diseases to determine, more generally, which programs, activities, and coping strategies can decrease caregiver challenges.^24-26 Further, understanding and addressing the needs of these families over many years will provide data that could inform policy, benefits, resources, and needed services (such as the Caregivers and Veterans Omnibus Health Services Act of 2010) and assist with family resilience efforts, including understanding and enhancing family protective and recovery factors.

As studies have indicated, some families do not report family distress when providing care to an individual with TBI. Understanding the factors that influence positive family adjustment is important to capture and perhaps replicate in future studies so that they can lead to effective treatment interventions. Although this review does not discuss caregiver needs for patients with TBI with disorders of consciousness that require more care than most caregivers can provide in the home setting, caregiving for this population deserves attention in future studies. Furthermore, an area that has not received much attention is the impact on children in the household. Children aged < 18 years can assist not only in the care of a disabled adult, but also of younger siblings; also they can help with household activities from housekeeping to meal preparation. Children also may provide physical and emotional support.

The impact of aging caregivers and subsequent needs for their own care as well as the person(s) they are providing care for has not been fully addressed. Areas requiring more research include both the aging caregiver taking care of an aging spouse or relative and the aging parent taking care of a young adult or child. Along with aging, the issue of long-term caregiving needs further development. For example, how do the differences between access to services between caregivers of adults with TBI in the military and those in the civilian sector impact the family/caregiver? Further research may answer questions such as:

• Which tools are most useful in evaluating and determining caregiver stress and burden?
• Are the needs of military and veteran caregivers unique?
• Do polytrauma patients with comorbid diagnoses have unique caregiver needs and trajectories?
• Do TBI caregiver stressors differ from stressors related to other medical conditions or chronic diseases?
• Is there a need for military and veteran TBI-specific caregiver programs?
• Which interventions best help caregivers and for how long?
• Should the approach to intervention depend on variables such as age and gender of the caregivers or relationship to the patient with a TBI (eg, spouse vs parent)?

Methods or processes to inform and update caregivers about available resources also are critically needed. Also, Sabab and colleagues noted the importance of research on the effects of denial as it relates to cognitive, emotional, social impact.²⁷ Denial may impact delays in treatments.

Resource

Many national, state, local, and grassroots organizations provide information and support for persons with illness and/or disabilities. Most clinicians of neurologic, mental health, and cancer have developed various forms of support interventions for those with the disease and their caregivers (Table 2). Highlighted in this section are a few organizations that specifically provide resources for caregivers caring for active-duty service members or veterans with a TBI.

Although a caregiver generally does not receive money from an outside source for services, the DoD may consider the caregiver as a nonmedical attendant for an active-duty service member and provide a temporary stipend. The VA provides several support and service options for caregivers under the Caregiver Support Program, through which more than 300 VA health care professionals provide support to caregivers. The Caregivers and Veterans Omnibus Health Services Act of 2010 authorizes the VA to provide additional VA services for seriously injured post-9/11 veterans and their family caregivers through the Program of Comprehensive Assistance for Family Caregivers (VA Caregiver Support Program). After meeting eligibility criteria, primary caregivers of post-9/11 veterans may receive a monthly stipend (based on the level of care needed) as well as comprehensive caregiver training, referral services, access to health care insurance, mental health services, counseling, and respite care. The Caregiver Support Program offers a toll-free support line and a 24-hour crisis hot line.

In 2014, the Government Accountability Office (GAO) outlined the VA health care improvements needed to manage the demand for the Caregiver Support Program, which are established at VA medical centers.²⁸ The GAO reported that the “VA significantly underestimated caregivers’ demand for services… larger than expected workloads and …delays in approval determinations” with about 500 approved caregivers who are added to the program each month. Original estimates indicated that about 4,000 caregivers would be approved by September 2014; however, by May 2014 about 15,600 caregivers were approved.

In addition to the VA Caregiver Support Program, a variety of state, local, and nonprofit organizations offer support for caregivers. Established in 2012, the Elizabeth Dole Foundation’s program Caring for Military Families “assists caregivers by raising awareness of the caregiver role, leveraging resources and partnerships to provide support, and identifying best practices and solutions to address the challenges caregivers face.” The foundation commissioned the RAND Corporation to “describe the magnitude of military caregiving in the United States, and to identify gaps in programs, policies, and services.” The 2014 RAND report estimated that among the 5.5 million military caregivers in the U.S., 1 million (19.6%) cared for post-9/11 veterans.²⁹ The military caregivers consistently experienced poorer health outcomes, greater strains on family relationships, and more workplace problems than noncaregivers; post-9/11 military caregivers fared worse in those areas.

The Elizabeth Dole Foundation, Hidden Heroes Impact Council Forum advocates for caregiver empowerment, cultural competency awareness, and better policies, programs, and services. The council focuses its efforts on key impact: community support at home, education and training, employment and workplace support, financial and legal issues, interfaith action and ministry council, mental and physical health, and respite care. It aims to raise the money to build awareness and support for military and veterans’ caregivers. The Military and Veteran Caregiver Network is another Elizabeth Dole Foundation initiative. It is an online forum community, peer support group, and peer mentor program structure. A resource library for referrals to local services also is available.

A variety of other organizations, such as United Service Organizations; Easter Seals; Team Red, White and Blue; Operation Homefront; Blue Star Families; state Brain Injury Associations; and support groups for TBI at local hospitals and community centers provide resources to both patients and caregivers. Organizations for caregivers not exclusive to TBI patients include the Caregiver Action Network (formerly National Family Caregiver Association) and the Family Caregiver Alliance. The National Family Caregivers Support Program provides grants to states and territories to develop and provide supportive services to caregivers. Some training for caregivers could include long-term financial planning, legal issues, residential and educational planning, caregiver stress management, the benefits of utilizing support resources, and actions and behaviors that enhance coping strategies. In 2007, DVBIC developed The Traumatic Brain Injury Guide for Caregivers of Service Members and Veterans, which is intended for family caregivers assisting a service member or veteran who sustained a moderate or severe TBI.⁶ A recent assessment determined the need to update the guide. The Center of Excellence for Medical Multimedia is another source of information for caregivers.

Conclusion

The recent combat conflicts of OEF and OIF have resulted in a dramatic increase in the occurrence of TBI injuries in active-duty service members both in theater and stateside and have highlighted the need for some service members and veterans with a TBI to require ongoing assistance from a caregiver. The levels of assistance and length of time vary greatly, impacted by the severity of the TBI and psychosocial situations.

In response to elevated awareness, several programs and resources have been developed or enhanced to address the specific needs of caregivers. Certain programs and resources are specific for caregivers of military service members and veterans, whereas others benefit caregivers in general. Likewise, some programs are not specific to individuals with TBI.

Caregivers assume many roles in their efforts to support the person with a TBI. They may need to dramatically adjust their lives to serve as a caregiver. Providing adequate resources for the caregivers impacts their ability to continue providing care. Thus, awareness of and access to resources play a critical role in helping to reduce stress, distress, burden (eg, physical, emotional, and financial), and caregiver burnout. Programs and resources often change, making it difficult for health care practitioners to know which programs offer what or even whether they still exist. Therefore, the authors synthesized the current medical literature of the topic of TBI and their caregiver needs as well as current resources for additional information and support.

Ongoing research studies, such as the congressionally mandated 15-year longitudinal study, are examining the impact of caregiving in the military and veteran communities. Future research could identify specific needs of military caregivers, identify gaps in services or programs, and identify interventions that promote resilience. Moreover, research directed at military and veteran caregivers can promote change that will benefit the general population of caregivers. It will be important for health care practitioners to keep abreast of new findings and information to incorporate into care plans for their patients who have had a TBI and their families.

Traumatic brain injury (TBI) is a health concern for the U.S. Military Health System (MHS) as well as the VHA. It occurs in both deployed and nondeployed settings; however, Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) and improved reporting mechanisms have dramatically increased TBI diagnoses in active-duty service members. According to the Defense and Veterans Brain Injury Center (DVBIC), more than 370,000 service members have been diagnosed with a TBI since 2000 (Figure).¹

Background

The DoD and the VA are collaborating on clinical research studies to identify, understand, and treat the long-term effects of TBI that can affect patients and their families. Most TBIs are mild (mTBIs), also called concussions, and patients typically recover within a few weeks (Table 1). However, some individuals with mTBI experience symptoms that may persist for months or years. A meta-analysis by Perry and colleagues showed that the prevalence or risk of a neurologic disorder, depression, or other mental health issue following mTBI was 67% higher compared with that in uninjured controls.²

Patients with any severity of TBI may require assistance with activities of daily living (ADLs), such as bathing, dressing, managing medications, and feeding. Patients also may need help with instrumental ADLs, such as meal preparation, grocery shopping, household chores, child care, getting to appointments or activities, coordination of educational and vocational services, financial and benefits management, and supportive listening.

Increased injuries have spurred the DoD and VA to coordinate health care to provide a seamless transition for patients between the 2 agencies. However, individuals who sustained a TBI may need various levels of caregiver assistance over time.

TBI and Caregivers

Despite better agency coordination for patients, caregivers can experience stress. Griffin and colleagues found that caregiving responsibilities can compete with other demands on the caregiver, such as work and family, and may negatively impact their health and finances.^3,4

Lou and colleagues studied the factors associated with caring for chronically ill family members that may result in stress for the caregivers.⁵ Along with an unaccounted for economic contribution, caregivers may face lost work time and pay and limitations on work travel and work advancement. Additionally, lost time for leisure, travel, social activities, family obligations, and retirement could result in physical and mental drain on the caregiver. Stress may reach a level at which the caregivers risk psychological distress. The study also noted that families with perceived high stress experience disrupted family functioning. Some TBI caregiver studies sought to understand how best to evaluate and determine the level of caregiver burden, and other studies investigated appropriate interventions.^6-9

Health care practitioners within the federal health care system may benefit from a greater awareness of caregiver needs and caregiver resources. Caregiver support can improve outcomes for both the caregiver and care recipient, and many organizations and resources already exist to assist the caregiver. This article reviews recent published literature on TBI caregivers of patients with TBI across civilian, military, and veteran populations and lists caregiver resources for additional information, assistance, and support.

Literature Review

The DVBIC defines the term caregiver as “any family or support person(s) relied upon by the service member or veteran with traumatic brain injury (TBI) who assumes primary responsibility for ensuring the needed level of care and overall well-being of that service member or veteran. A family or family caregiver may include spouse, parents, children, other extended family members, as well as significant others and friends.”³

In the following discussion, findings from military and veteran literature are separated from civilian population findings to highlight similarities and differences between these 2 bodies of research. Several of the studies in the military/veteran cohorts include polytrauma patients with comorbid physical and mental health issues not necessarily found in civilian literature.

Civilian Literature

A 2015 systematic review by Anderson and colleagues on coping and psychological adjustment in TBI caregivers indicated no Class I or Class II studies.¹⁰ Four Class III and 3 Class IV studies were found. The authors suggest that more rigorous studies (ie, Class I and II) are needed.

Despite these limitations, peer-reviewed literature indicates that the levels of stress and distress in TBI caregivers are consistent with reports for other diseases. In a civilian population, Carlozzi and colleagues found that TBI caregivers who reported stress, distress, anxiety, and feeling overwhelmed often had concerns for their social, emotional, physical, cognitive health, as well as feelings of loss.⁵ In addition, caregivers may need to take leaves of absence or leave the workforce entirely to provide for a family member or friend who had a TBI—often leading to financial strain (eg, depleting assets, accumulating debt). These challenges may occur during prime earning years, and the caregiver may lose the ability to resume work if the care receiver requires care for extended periods.¹¹

Kratz and colleagues showed that caregivers of individuals with moderate-to-severe TBI: (1) felt overburdened with responsibilities; (2) lacked personal time and time for self-care; (3) felt their lives were interrupted or lost; (4) grieved the loss of the person with TBI; and (5) endorsed anger, guilt, anxiety, and sadness.¹²

Perceptions differed between caregiver parents and caregiver partners. Parents expressed feelings of grief and sadness related to the “loss of the person before the TBI.” Parents also reported a sense of guilt and responsibility for their child’s TBI and feelings of being tied down to the individual with TBI. Parents experienced a greater level of stress if the son or daughter with TBI still lived at home. Partners expressed frustration and despair related to their role as sole decision maker and care provider. Partners’ distress also related to the partner relationship and the relationship between children and the individual with TBI.

Verhasghe and colleagues found that partners experience a greater degree of stress than do parents.¹³ Young families with minimal social support for coping with financial, psychiatric, and medical problems were the most vulnerable to stress. A systematic review by Ennis and colleagues evaluated depression and anxiety in caregiver parents vs spouses.¹⁴ Although methods and quality differed in the studies, findings indicated high levels of distress regardless of the type of caregiver.

Anderson and colleagues used the Ways of Coping Questionnaire to evaluate the association between coping and psychological adjustment in caregivers of TBI individuals.¹⁰ The use of emotion-focused coping and problem solving was possibly associated with psychological adjustment in caregivers. Verhasghe and colleagues indicated that the nature of the injuries more than the severity of TBI determined the level of stress up to 15 years after the TBI.¹³ Gender and social and professional support also influenced coping. The review identified the need to develop models of long-term support and care.

An Australian cohort of 79 family caregivers participated in a study by Perlesz and colleagues.¹⁵ Participants’ caregiving responsibilities averaged 19.3 months posttrauma. The Family Satisfaction Scale, Beck Depression Inventory, State Anxiety Inventory, and Profile of Mood States were used in this analysis. Male caregivers reported distress in terms of anger and fatigue; female caregivers were at greatest risk of poor psychosocial outcomes. Although findings from primary caregivers indicated that 35% to 49% displayed enough distress to warrant clinical intervention, between 51% and 80% were not psychologically distressed and were satisfied with their families. Data supported previous reports suggesting caregivers are “not universally distressed.”¹⁵

Manskow and colleagues followed patients with severe TBI and assessed caregiver burden 1 year later. Using the Caregiver Burden Scale, caregivers reported the highest scores (N = 92) on the General Strain Index followed by the Disappointment Index.¹⁶ Bayen and colleagues also studied caregivers of severe TBI patients.¹⁷ Objective and subjective caregiver burden data 4 years later indicated 44% of caregivers (N = 98) reported multidimensional burden. Greater burden was associated in caring for individuals who had poorer Glasgow Outcome Scale Extended scores and more severe cognitive disorders.

Military and Veteran Literature

Griffin and colleagues conducted the Family and Caregiver Experience Study (FACES) with caregivers (N = 564) of service members who incurred a TBI.³ According to the caregivers, two-thirds of the patients lost consciousness for more than 30 minutes, which was followed by inpatient rehabilitation care at a VA polytrauma center between 2001 and 2009. The majority of caregivers of TBI patients were female (79%) and aged < 60 years (84%). Parents comprised 62% and spouses 32% of the cohort. Caregivers tended to have some level of education beyond high school (73%), were married (77%), either worked or were enrolled in school (55%), and earned less than $40,000 a year (70%). Common characteristics of the care receivers were male gender (95%), average age 30, high school educated (52%), married (almost 50%), and employed (50%). Forty-five percent of the care receivers were injured 4 to 6 years prior, and 12% were injured 7 or more years prior. The study determined the caregivers’ perception of intensity of care needed and indicated that families as well as clinicians need to plan for some level of long-term support and services.

In addition to the TBI-related caregiving needs, Griffin and colleagues found in a military population that other medical conditions impacted the level of caregiving and strained a marriage.¹⁸ Their study found that in a military population between 30% and 50% of marriages of patients with TBI dissolved within the first 10 years after injury. Caregivers may need to learn nursing activities, such as tube feedings, tracheostomy and stoma care, catheter care, wound care, and medication administration. Family stress with caregiving may interfere with the ability to understand information related to the care receivers’ medical care and may require multiple formats to explain care needs. Sander and colleagues associated better emotional functioning in caregivers with greater social integration and occupation outcomes in patients at the postacute rehabilitation program phase (within 6 months of injury).¹⁹ However, these outcomes did not continue more than 6 months postinjury.

Intervention and Research Studies

Powell and colleagues used a telephone-based, individualized TBI education intervention along with problem-solving mentoring (10 phone calls at 2-week intervals following patient discharge for moderate-to-severe TBI from a level 1 trauma center) to determine which programs, activities, and coping strategies could decrease caregiver challenges.²⁰ The telephone interventions resulted in better caregiver outcomes than usual care as measured by composite scores on the Bakas Caregiving Outcomes Scale (BCOS) and the Brief Symptom Inventory (BSI-18) at 6 months post-TBI survivor discharge. Dyer and colleagues explored Internet approaches and mobile applications to provide support for caregivers. ¹⁸ In a small sample of 10 caregivers, Damianakis and colleagues conducted a 10-session pilot videoconferencing support-group intervention program led by a clinician. Results indicated that the intervention enhanced caregiver coping and problem-solving skills.⁷

Petranovich and colleagues examined the efficacy of counselor-assisted problem-solving interventions in improving long-term caregiver psychological functioning following TBI in adolescents.²¹ Their findings support the utility of online interventions in improving long-term caregiver psychological distress, particularly for lower income families. Although this study focused on adolescents, research may indicate merit in an adult population. In relatives of patients with severe TBI, Norup and colleagues associated improvements in health-related quality of life (HRQOL) with improvements in symptoms of anxiety and depression without specific intervention.²²

Moriarty and colleagues conducted a randomized controlled trial for veterans who received care at a VA polytrauma center and their family members who participated in a veteran’s in-home program (VIP) intervention.⁹ The study aimed to evaluate how VIP affected family members’ caregiver burden, depressive symptoms, satisfaction with caregiving, and the program’s acceptability. Eighty-one veterans with a key family member were randomized. Of those, 63 veterans completed a follow-up interview. The intervention consisted of 6 home visits of 1 to 2 hours each and 2 telephone calls from an occupational therapist over 3 to 4 months. Family members were invited to participate during the home visits. The control group received usual clinic care with 2 telephone calls during the study period. All participants received the follow-up interview 3 to 4 months after baseline interviews. The severity of TBI was determined by a review of the electronic medical record using the VA/DoD Clinical Practice Guidelines. Findings of this study indicated that family members in the intervention group showed significantly lower depressive symptom scores and caregiver burden scores.⁹ Additionally, the veterans in the intervention group exhibited higher community integration and ability to manage their targeted outcomes. Further research may indicate that VIP could assist patients with TBI and caregivers in an active-duty population.

The DVBIC is the executive agent for a congressionally mandated 15-year longitudinal study on TBI incurred by members of the armed services in OEF and OIF. The John Warner National Defense Authorization Act for Fiscal Year 2007 outlined the study. An initial finding identified the need for an HRQOL outcomes assessment specific to TBI caregivers.²³ Having these data will allow investigators to fully determine the comprehensive impact of caring for a person who sustained a mild, moderate, severe, or penetrating TBI and to evaluate the effectiveness of interventions designed to address caregivers’ needs. To date, the study has identified the following HRQOL themes generated among caregivers: social health, emotional health, physical/medical health, cognitive functioning, and feelings of loss (related to changing social roles). Carlozzi and colleagues noted that the study also aimed to identify a sensitive outcome measure to evaluate quality of life in the caregivers over time.⁷

Knowledge Gaps

Ongoing studies focus on caregiving for individuals with various illnesses and needs. Some of the information in each study may be beneficial to TBI caregivers who are not fully aware of resources and interventions. For example, Fortune and colleagues, Hirano and colleagues, and Grover and colleagues are studying caregiver activities involving other diseases to determine, more generally, which programs, activities, and coping strategies can decrease caregiver challenges.^24-26 Further, understanding and addressing the needs of these families over many years will provide data that could inform policy, benefits, resources, and needed services (such as the Caregivers and Veterans Omnibus Health Services Act of 2010) and assist with family resilience efforts, including understanding and enhancing family protective and recovery factors.

As studies have indicated, some families do not report family distress when providing care to an individual with TBI. Understanding the factors that influence positive family adjustment is important to capture and perhaps replicate in future studies so that they can lead to effective treatment interventions. Although this review does not discuss caregiver needs for patients with TBI with disorders of consciousness that require more care than most caregivers can provide in the home setting, caregiving for this population deserves attention in future studies. Furthermore, an area that has not received much attention is the impact on children in the household. Children aged < 18 years can assist not only in the care of a disabled adult, but also of younger siblings; also they can help with household activities from housekeeping to meal preparation. Children also may provide physical and emotional support.

The impact of aging caregivers and subsequent needs for their own care as well as the person(s) they are providing care for has not been fully addressed. Areas requiring more research include both the aging caregiver taking care of an aging spouse or relative and the aging parent taking care of a young adult or child. Along with aging, the issue of long-term caregiving needs further development. For example, how do the differences between access to services between caregivers of adults with TBI in the military and those in the civilian sector impact the family/caregiver? Further research may answer questions such as:

• Which tools are most useful in evaluating and determining caregiver stress and burden?
• Are the needs of military and veteran caregivers unique?
• Do polytrauma patients with comorbid diagnoses have unique caregiver needs and trajectories?
• Do TBI caregiver stressors differ from stressors related to other medical conditions or chronic diseases?
• Is there a need for military and veteran TBI-specific caregiver programs?
• Which interventions best help caregivers and for how long?
• Should the approach to intervention depend on variables such as age and gender of the caregivers or relationship to the patient with a TBI (eg, spouse vs parent)?

Methods or processes to inform and update caregivers about available resources also are critically needed. Also, Sabab and colleagues noted the importance of research on the effects of denial as it relates to cognitive, emotional, social impact.²⁷ Denial may impact delays in treatments.

Resource

Many national, state, local, and grassroots organizations provide information and support for persons with illness and/or disabilities. Most clinicians of neurologic, mental health, and cancer have developed various forms of support interventions for those with the disease and their caregivers (Table 2). Highlighted in this section are a few organizations that specifically provide resources for caregivers caring for active-duty service members or veterans with a TBI.

Although a caregiver generally does not receive money from an outside source for services, the DoD may consider the caregiver as a nonmedical attendant for an active-duty service member and provide a temporary stipend. The VA provides several support and service options for caregivers under the Caregiver Support Program, through which more than 300 VA health care professionals provide support to caregivers. The Caregivers and Veterans Omnibus Health Services Act of 2010 authorizes the VA to provide additional VA services for seriously injured post-9/11 veterans and their family caregivers through the Program of Comprehensive Assistance for Family Caregivers (VA Caregiver Support Program). After meeting eligibility criteria, primary caregivers of post-9/11 veterans may receive a monthly stipend (based on the level of care needed) as well as comprehensive caregiver training, referral services, access to health care insurance, mental health services, counseling, and respite care. The Caregiver Support Program offers a toll-free support line and a 24-hour crisis hot line.

In 2014, the Government Accountability Office (GAO) outlined the VA health care improvements needed to manage the demand for the Caregiver Support Program, which are established at VA medical centers.²⁸ The GAO reported that the “VA significantly underestimated caregivers’ demand for services… larger than expected workloads and …delays in approval determinations” with about 500 approved caregivers who are added to the program each month. Original estimates indicated that about 4,000 caregivers would be approved by September 2014; however, by May 2014 about 15,600 caregivers were approved.

In addition to the VA Caregiver Support Program, a variety of state, local, and nonprofit organizations offer support for caregivers. Established in 2012, the Elizabeth Dole Foundation’s program Caring for Military Families “assists caregivers by raising awareness of the caregiver role, leveraging resources and partnerships to provide support, and identifying best practices and solutions to address the challenges caregivers face.” The foundation commissioned the RAND Corporation to “describe the magnitude of military caregiving in the United States, and to identify gaps in programs, policies, and services.” The 2014 RAND report estimated that among the 5.5 million military caregivers in the U.S., 1 million (19.6%) cared for post-9/11 veterans.²⁹ The military caregivers consistently experienced poorer health outcomes, greater strains on family relationships, and more workplace problems than noncaregivers; post-9/11 military caregivers fared worse in those areas.

The Elizabeth Dole Foundation, Hidden Heroes Impact Council Forum advocates for caregiver empowerment, cultural competency awareness, and better policies, programs, and services. The council focuses its efforts on key impact: community support at home, education and training, employment and workplace support, financial and legal issues, interfaith action and ministry council, mental and physical health, and respite care. It aims to raise the money to build awareness and support for military and veterans’ caregivers. The Military and Veteran Caregiver Network is another Elizabeth Dole Foundation initiative. It is an online forum community, peer support group, and peer mentor program structure. A resource library for referrals to local services also is available.

A variety of other organizations, such as United Service Organizations; Easter Seals; Team Red, White and Blue; Operation Homefront; Blue Star Families; state Brain Injury Associations; and support groups for TBI at local hospitals and community centers provide resources to both patients and caregivers. Organizations for caregivers not exclusive to TBI patients include the Caregiver Action Network (formerly National Family Caregiver Association) and the Family Caregiver Alliance. The National Family Caregivers Support Program provides grants to states and territories to develop and provide supportive services to caregivers. Some training for caregivers could include long-term financial planning, legal issues, residential and educational planning, caregiver stress management, the benefits of utilizing support resources, and actions and behaviors that enhance coping strategies. In 2007, DVBIC developed The Traumatic Brain Injury Guide for Caregivers of Service Members and Veterans, which is intended for family caregivers assisting a service member or veteran who sustained a moderate or severe TBI.⁶ A recent assessment determined the need to update the guide. The Center of Excellence for Medical Multimedia is another source of information for caregivers.

Conclusion

The recent combat conflicts of OEF and OIF have resulted in a dramatic increase in the occurrence of TBI injuries in active-duty service members both in theater and stateside and have highlighted the need for some service members and veterans with a TBI to require ongoing assistance from a caregiver. The levels of assistance and length of time vary greatly, impacted by the severity of the TBI and psychosocial situations.

In response to elevated awareness, several programs and resources have been developed or enhanced to address the specific needs of caregivers. Certain programs and resources are specific for caregivers of military service members and veterans, whereas others benefit caregivers in general. Likewise, some programs are not specific to individuals with TBI.

Caregivers assume many roles in their efforts to support the person with a TBI. They may need to dramatically adjust their lives to serve as a caregiver. Providing adequate resources for the caregivers impacts their ability to continue providing care. Thus, awareness of and access to resources play a critical role in helping to reduce stress, distress, burden (eg, physical, emotional, and financial), and caregiver burnout. Programs and resources often change, making it difficult for health care practitioners to know which programs offer what or even whether they still exist. Therefore, the authors synthesized the current medical literature of the topic of TBI and their caregiver needs as well as current resources for additional information and support.

Ongoing research studies, such as the congressionally mandated 15-year longitudinal study, are examining the impact of caregiving in the military and veteran communities. Future research could identify specific needs of military caregivers, identify gaps in services or programs, and identify interventions that promote resilience. Moreover, research directed at military and veteran caregivers can promote change that will benefit the general population of caregivers. It will be important for health care practitioners to keep abreast of new findings and information to incorporate into care plans for their patients who have had a TBI and their families.

Traumatic brain injury (TBI) is a health concern for the U.S. Military Health System (MHS) as well as the VHA. It occurs in both deployed and nondeployed settings; however, Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) and improved reporting mechanisms have dramatically increased TBI diagnoses in active-duty service members. According to the Defense and Veterans Brain Injury Center (DVBIC), more than 370,000 service members have been diagnosed with a TBI since 2000 (Figure).¹

Background

The DoD and the VA are collaborating on clinical research studies to identify, understand, and treat the long-term effects of TBI that can affect patients and their families. Most TBIs are mild (mTBIs), also called concussions, and patients typically recover within a few weeks (Table 1). However, some individuals with mTBI experience symptoms that may persist for months or years. A meta-analysis by Perry and colleagues showed that the prevalence or risk of a neurologic disorder, depression, or other mental health issue following mTBI was 67% higher compared with that in uninjured controls.²

Patients with any severity of TBI may require assistance with activities of daily living (ADLs), such as bathing, dressing, managing medications, and feeding. Patients also may need help with instrumental ADLs, such as meal preparation, grocery shopping, household chores, child care, getting to appointments or activities, coordination of educational and vocational services, financial and benefits management, and supportive listening.

Increased injuries have spurred the DoD and VA to coordinate health care to provide a seamless transition for patients between the 2 agencies. However, individuals who sustained a TBI may need various levels of caregiver assistance over time.

TBI and Caregivers

Despite better agency coordination for patients, caregivers can experience stress. Griffin and colleagues found that caregiving responsibilities can compete with other demands on the caregiver, such as work and family, and may negatively impact their health and finances.^3,4

Lou and colleagues studied the factors associated with caring for chronically ill family members that may result in stress for the caregivers.⁵ Along with an unaccounted for economic contribution, caregivers may face lost work time and pay and limitations on work travel and work advancement. Additionally, lost time for leisure, travel, social activities, family obligations, and retirement could result in physical and mental drain on the caregiver. Stress may reach a level at which the caregivers risk psychological distress. The study also noted that families with perceived high stress experience disrupted family functioning. Some TBI caregiver studies sought to understand how best to evaluate and determine the level of caregiver burden, and other studies investigated appropriate interventions.^6-9

Health care practitioners within the federal health care system may benefit from a greater awareness of caregiver needs and caregiver resources. Caregiver support can improve outcomes for both the caregiver and care recipient, and many organizations and resources already exist to assist the caregiver. This article reviews recent published literature on TBI caregivers of patients with TBI across civilian, military, and veteran populations and lists caregiver resources for additional information, assistance, and support.

Literature Review

The DVBIC defines the term caregiver as “any family or support person(s) relied upon by the service member or veteran with traumatic brain injury (TBI) who assumes primary responsibility for ensuring the needed level of care and overall well-being of that service member or veteran. A family or family caregiver may include spouse, parents, children, other extended family members, as well as significant others and friends.”³

In the following discussion, findings from military and veteran literature are separated from civilian population findings to highlight similarities and differences between these 2 bodies of research. Several of the studies in the military/veteran cohorts include polytrauma patients with comorbid physical and mental health issues not necessarily found in civilian literature.

Civilian Literature

A 2015 systematic review by Anderson and colleagues on coping and psychological adjustment in TBI caregivers indicated no Class I or Class II studies.¹⁰ Four Class III and 3 Class IV studies were found. The authors suggest that more rigorous studies (ie, Class I and II) are needed.

Despite these limitations, peer-reviewed literature indicates that the levels of stress and distress in TBI caregivers are consistent with reports for other diseases. In a civilian population, Carlozzi and colleagues found that TBI caregivers who reported stress, distress, anxiety, and feeling overwhelmed often had concerns for their social, emotional, physical, cognitive health, as well as feelings of loss.⁵ In addition, caregivers may need to take leaves of absence or leave the workforce entirely to provide for a family member or friend who had a TBI—often leading to financial strain (eg, depleting assets, accumulating debt). These challenges may occur during prime earning years, and the caregiver may lose the ability to resume work if the care receiver requires care for extended periods.¹¹

Kratz and colleagues showed that caregivers of individuals with moderate-to-severe TBI: (1) felt overburdened with responsibilities; (2) lacked personal time and time for self-care; (3) felt their lives were interrupted or lost; (4) grieved the loss of the person with TBI; and (5) endorsed anger, guilt, anxiety, and sadness.¹²

Perceptions differed between caregiver parents and caregiver partners. Parents expressed feelings of grief and sadness related to the “loss of the person before the TBI.” Parents also reported a sense of guilt and responsibility for their child’s TBI and feelings of being tied down to the individual with TBI. Parents experienced a greater level of stress if the son or daughter with TBI still lived at home. Partners expressed frustration and despair related to their role as sole decision maker and care provider. Partners’ distress also related to the partner relationship and the relationship between children and the individual with TBI.

Verhasghe and colleagues found that partners experience a greater degree of stress than do parents.¹³ Young families with minimal social support for coping with financial, psychiatric, and medical problems were the most vulnerable to stress. A systematic review by Ennis and colleagues evaluated depression and anxiety in caregiver parents vs spouses.¹⁴ Although methods and quality differed in the studies, findings indicated high levels of distress regardless of the type of caregiver.

Anderson and colleagues used the Ways of Coping Questionnaire to evaluate the association between coping and psychological adjustment in caregivers of TBI individuals.¹⁰ The use of emotion-focused coping and problem solving was possibly associated with psychological adjustment in caregivers. Verhasghe and colleagues indicated that the nature of the injuries more than the severity of TBI determined the level of stress up to 15 years after the TBI.¹³ Gender and social and professional support also influenced coping. The review identified the need to develop models of long-term support and care.

An Australian cohort of 79 family caregivers participated in a study by Perlesz and colleagues.¹⁵ Participants’ caregiving responsibilities averaged 19.3 months posttrauma. The Family Satisfaction Scale, Beck Depression Inventory, State Anxiety Inventory, and Profile of Mood States were used in this analysis. Male caregivers reported distress in terms of anger and fatigue; female caregivers were at greatest risk of poor psychosocial outcomes. Although findings from primary caregivers indicated that 35% to 49% displayed enough distress to warrant clinical intervention, between 51% and 80% were not psychologically distressed and were satisfied with their families. Data supported previous reports suggesting caregivers are “not universally distressed.”¹⁵

Manskow and colleagues followed patients with severe TBI and assessed caregiver burden 1 year later. Using the Caregiver Burden Scale, caregivers reported the highest scores (N = 92) on the General Strain Index followed by the Disappointment Index.¹⁶ Bayen and colleagues also studied caregivers of severe TBI patients.¹⁷ Objective and subjective caregiver burden data 4 years later indicated 44% of caregivers (N = 98) reported multidimensional burden. Greater burden was associated in caring for individuals who had poorer Glasgow Outcome Scale Extended scores and more severe cognitive disorders.

Military and Veteran Literature

Griffin and colleagues conducted the Family and Caregiver Experience Study (FACES) with caregivers (N = 564) of service members who incurred a TBI.³ According to the caregivers, two-thirds of the patients lost consciousness for more than 30 minutes, which was followed by inpatient rehabilitation care at a VA polytrauma center between 2001 and 2009. The majority of caregivers of TBI patients were female (79%) and aged < 60 years (84%). Parents comprised 62% and spouses 32% of the cohort. Caregivers tended to have some level of education beyond high school (73%), were married (77%), either worked or were enrolled in school (55%), and earned less than $40,000 a year (70%). Common characteristics of the care receivers were male gender (95%), average age 30, high school educated (52%), married (almost 50%), and employed (50%). Forty-five percent of the care receivers were injured 4 to 6 years prior, and 12% were injured 7 or more years prior. The study determined the caregivers’ perception of intensity of care needed and indicated that families as well as clinicians need to plan for some level of long-term support and services.

In addition to the TBI-related caregiving needs, Griffin and colleagues found in a military population that other medical conditions impacted the level of caregiving and strained a marriage.¹⁸ Their study found that in a military population between 30% and 50% of marriages of patients with TBI dissolved within the first 10 years after injury. Caregivers may need to learn nursing activities, such as tube feedings, tracheostomy and stoma care, catheter care, wound care, and medication administration. Family stress with caregiving may interfere with the ability to understand information related to the care receivers’ medical care and may require multiple formats to explain care needs. Sander and colleagues associated better emotional functioning in caregivers with greater social integration and occupation outcomes in patients at the postacute rehabilitation program phase (within 6 months of injury).¹⁹ However, these outcomes did not continue more than 6 months postinjury.

Intervention and Research Studies

Powell and colleagues used a telephone-based, individualized TBI education intervention along with problem-solving mentoring (10 phone calls at 2-week intervals following patient discharge for moderate-to-severe TBI from a level 1 trauma center) to determine which programs, activities, and coping strategies could decrease caregiver challenges.²⁰ The telephone interventions resulted in better caregiver outcomes than usual care as measured by composite scores on the Bakas Caregiving Outcomes Scale (BCOS) and the Brief Symptom Inventory (BSI-18) at 6 months post-TBI survivor discharge. Dyer and colleagues explored Internet approaches and mobile applications to provide support for caregivers. ¹⁸ In a small sample of 10 caregivers, Damianakis and colleagues conducted a 10-session pilot videoconferencing support-group intervention program led by a clinician. Results indicated that the intervention enhanced caregiver coping and problem-solving skills.⁷

Petranovich and colleagues examined the efficacy of counselor-assisted problem-solving interventions in improving long-term caregiver psychological functioning following TBI in adolescents.²¹ Their findings support the utility of online interventions in improving long-term caregiver psychological distress, particularly for lower income families. Although this study focused on adolescents, research may indicate merit in an adult population. In relatives of patients with severe TBI, Norup and colleagues associated improvements in health-related quality of life (HRQOL) with improvements in symptoms of anxiety and depression without specific intervention.²²

Moriarty and colleagues conducted a randomized controlled trial for veterans who received care at a VA polytrauma center and their family members who participated in a veteran’s in-home program (VIP) intervention.⁹ The study aimed to evaluate how VIP affected family members’ caregiver burden, depressive symptoms, satisfaction with caregiving, and the program’s acceptability. Eighty-one veterans with a key family member were randomized. Of those, 63 veterans completed a follow-up interview. The intervention consisted of 6 home visits of 1 to 2 hours each and 2 telephone calls from an occupational therapist over 3 to 4 months. Family members were invited to participate during the home visits. The control group received usual clinic care with 2 telephone calls during the study period. All participants received the follow-up interview 3 to 4 months after baseline interviews. The severity of TBI was determined by a review of the electronic medical record using the VA/DoD Clinical Practice Guidelines. Findings of this study indicated that family members in the intervention group showed significantly lower depressive symptom scores and caregiver burden scores.⁹ Additionally, the veterans in the intervention group exhibited higher community integration and ability to manage their targeted outcomes. Further research may indicate that VIP could assist patients with TBI and caregivers in an active-duty population.

The DVBIC is the executive agent for a congressionally mandated 15-year longitudinal study on TBI incurred by members of the armed services in OEF and OIF. The John Warner National Defense Authorization Act for Fiscal Year 2007 outlined the study. An initial finding identified the need for an HRQOL outcomes assessment specific to TBI caregivers.²³ Having these data will allow investigators to fully determine the comprehensive impact of caring for a person who sustained a mild, moderate, severe, or penetrating TBI and to evaluate the effectiveness of interventions designed to address caregivers’ needs. To date, the study has identified the following HRQOL themes generated among caregivers: social health, emotional health, physical/medical health, cognitive functioning, and feelings of loss (related to changing social roles). Carlozzi and colleagues noted that the study also aimed to identify a sensitive outcome measure to evaluate quality of life in the caregivers over time.⁷

Knowledge Gaps

Ongoing studies focus on caregiving for individuals with various illnesses and needs. Some of the information in each study may be beneficial to TBI caregivers who are not fully aware of resources and interventions. For example, Fortune and colleagues, Hirano and colleagues, and Grover and colleagues are studying caregiver activities involving other diseases to determine, more generally, which programs, activities, and coping strategies can decrease caregiver challenges.^24-26 Further, understanding and addressing the needs of these families over many years will provide data that could inform policy, benefits, resources, and needed services (such as the Caregivers and Veterans Omnibus Health Services Act of 2010) and assist with family resilience efforts, including understanding and enhancing family protective and recovery factors.

As studies have indicated, some families do not report family distress when providing care to an individual with TBI. Understanding the factors that influence positive family adjustment is important to capture and perhaps replicate in future studies so that they can lead to effective treatment interventions. Although this review does not discuss caregiver needs for patients with TBI with disorders of consciousness that require more care than most caregivers can provide in the home setting, caregiving for this population deserves attention in future studies. Furthermore, an area that has not received much attention is the impact on children in the household. Children aged < 18 years can assist not only in the care of a disabled adult, but also of younger siblings; also they can help with household activities from housekeeping to meal preparation. Children also may provide physical and emotional support.

The impact of aging caregivers and subsequent needs for their own care as well as the person(s) they are providing care for has not been fully addressed. Areas requiring more research include both the aging caregiver taking care of an aging spouse or relative and the aging parent taking care of a young adult or child. Along with aging, the issue of long-term caregiving needs further development. For example, how do the differences between access to services between caregivers of adults with TBI in the military and those in the civilian sector impact the family/caregiver? Further research may answer questions such as:

• Which tools are most useful in evaluating and determining caregiver stress and burden?
• Are the needs of military and veteran caregivers unique?
• Do polytrauma patients with comorbid diagnoses have unique caregiver needs and trajectories?
• Do TBI caregiver stressors differ from stressors related to other medical conditions or chronic diseases?
• Is there a need for military and veteran TBI-specific caregiver programs?
• Which interventions best help caregivers and for how long?
• Should the approach to intervention depend on variables such as age and gender of the caregivers or relationship to the patient with a TBI (eg, spouse vs parent)?

Methods or processes to inform and update caregivers about available resources also are critically needed. Also, Sabab and colleagues noted the importance of research on the effects of denial as it relates to cognitive, emotional, social impact.²⁷ Denial may impact delays in treatments.

Resource

Many national, state, local, and grassroots organizations provide information and support for persons with illness and/or disabilities. Most clinicians of neurologic, mental health, and cancer have developed various forms of support interventions for those with the disease and their caregivers (Table 2). Highlighted in this section are a few organizations that specifically provide resources for caregivers caring for active-duty service members or veterans with a TBI.

Although a caregiver generally does not receive money from an outside source for services, the DoD may consider the caregiver as a nonmedical attendant for an active-duty service member and provide a temporary stipend. The VA provides several support and service options for caregivers under the Caregiver Support Program, through which more than 300 VA health care professionals provide support to caregivers. The Caregivers and Veterans Omnibus Health Services Act of 2010 authorizes the VA to provide additional VA services for seriously injured post-9/11 veterans and their family caregivers through the Program of Comprehensive Assistance for Family Caregivers (VA Caregiver Support Program). After meeting eligibility criteria, primary caregivers of post-9/11 veterans may receive a monthly stipend (based on the level of care needed) as well as comprehensive caregiver training, referral services, access to health care insurance, mental health services, counseling, and respite care. The Caregiver Support Program offers a toll-free support line and a 24-hour crisis hot line.

In 2014, the Government Accountability Office (GAO) outlined the VA health care improvements needed to manage the demand for the Caregiver Support Program, which are established at VA medical centers.²⁸ The GAO reported that the “VA significantly underestimated caregivers’ demand for services… larger than expected workloads and …delays in approval determinations” with about 500 approved caregivers who are added to the program each month. Original estimates indicated that about 4,000 caregivers would be approved by September 2014; however, by May 2014 about 15,600 caregivers were approved.

In addition to the VA Caregiver Support Program, a variety of state, local, and nonprofit organizations offer support for caregivers. Established in 2012, the Elizabeth Dole Foundation’s program Caring for Military Families “assists caregivers by raising awareness of the caregiver role, leveraging resources and partnerships to provide support, and identifying best practices and solutions to address the challenges caregivers face.” The foundation commissioned the RAND Corporation to “describe the magnitude of military caregiving in the United States, and to identify gaps in programs, policies, and services.” The 2014 RAND report estimated that among the 5.5 million military caregivers in the U.S., 1 million (19.6%) cared for post-9/11 veterans.²⁹ The military caregivers consistently experienced poorer health outcomes, greater strains on family relationships, and more workplace problems than noncaregivers; post-9/11 military caregivers fared worse in those areas.

The Elizabeth Dole Foundation, Hidden Heroes Impact Council Forum advocates for caregiver empowerment, cultural competency awareness, and better policies, programs, and services. The council focuses its efforts on key impact: community support at home, education and training, employment and workplace support, financial and legal issues, interfaith action and ministry council, mental and physical health, and respite care. It aims to raise the money to build awareness and support for military and veterans’ caregivers. The Military and Veteran Caregiver Network is another Elizabeth Dole Foundation initiative. It is an online forum community, peer support group, and peer mentor program structure. A resource library for referrals to local services also is available.

A variety of other organizations, such as United Service Organizations; Easter Seals; Team Red, White and Blue; Operation Homefront; Blue Star Families; state Brain Injury Associations; and support groups for TBI at local hospitals and community centers provide resources to both patients and caregivers. Organizations for caregivers not exclusive to TBI patients include the Caregiver Action Network (formerly National Family Caregiver Association) and the Family Caregiver Alliance. The National Family Caregivers Support Program provides grants to states and territories to develop and provide supportive services to caregivers. Some training for caregivers could include long-term financial planning, legal issues, residential and educational planning, caregiver stress management, the benefits of utilizing support resources, and actions and behaviors that enhance coping strategies. In 2007, DVBIC developed The Traumatic Brain Injury Guide for Caregivers of Service Members and Veterans, which is intended for family caregivers assisting a service member or veteran who sustained a moderate or severe TBI.⁶ A recent assessment determined the need to update the guide. The Center of Excellence for Medical Multimedia is another source of information for caregivers.

Conclusion

The recent combat conflicts of OEF and OIF have resulted in a dramatic increase in the occurrence of TBI injuries in active-duty service members both in theater and stateside and have highlighted the need for some service members and veterans with a TBI to require ongoing assistance from a caregiver. The levels of assistance and length of time vary greatly, impacted by the severity of the TBI and psychosocial situations.

In response to elevated awareness, several programs and resources have been developed or enhanced to address the specific needs of caregivers. Certain programs and resources are specific for caregivers of military service members and veterans, whereas others benefit caregivers in general. Likewise, some programs are not specific to individuals with TBI.

Caregivers assume many roles in their efforts to support the person with a TBI. They may need to dramatically adjust their lives to serve as a caregiver. Providing adequate resources for the caregivers impacts their ability to continue providing care. Thus, awareness of and access to resources play a critical role in helping to reduce stress, distress, burden (eg, physical, emotional, and financial), and caregiver burnout. Programs and resources often change, making it difficult for health care practitioners to know which programs offer what or even whether they still exist. Therefore, the authors synthesized the current medical literature of the topic of TBI and their caregiver needs as well as current resources for additional information and support.

Ongoing research studies, such as the congressionally mandated 15-year longitudinal study, are examining the impact of caregiving in the military and veteran communities. Future research could identify specific needs of military caregivers, identify gaps in services or programs, and identify interventions that promote resilience. Moreover, research directed at military and veteran caregivers can promote change that will benefit the general population of caregivers. It will be important for health care practitioners to keep abreast of new findings and information to incorporate into care plans for their patients who have had a TBI and their families.

© Phil McCarten 2017

ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).

Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.

In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.

The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.

bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).

BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.

Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).

Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.

Study design

Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.

BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.

The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 10⁶, 150 x 10⁶, 450 x 10⁶, and 800 x 10⁶.

Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.

“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.

Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²).

Patient characteristics

Investigators dosed 21 patients as of the data cut-off of October 2.

Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.

All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).

“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”

All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.

Safety

“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”

The investigators observed no dose-limiting toxicities.

Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.

Five (24%) patients experienced neurotoxicity, none grade 3 or higher.

Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.

The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.

The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.

“By day 17, she dramatically improved,” Dr Kochenderfer said.

Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.

On day 30, the patient was out of the intensive care unit.

“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”

Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.

Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.

Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.

Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.

Efficacy

In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.

The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.

The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.

“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”

The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.

The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.

Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.

“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.

However, he noted that the patients are eligible for re-treatment.

Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.

The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.

*Data presented differ from the abstract.

© Phil McCarten 2017

ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).

Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.

In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.

The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.

bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).

BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.

Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).

Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.

Study design

Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.

BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.

The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 10⁶, 150 x 10⁶, 450 x 10⁶, and 800 x 10⁶.

Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.

“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.

Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²).

Patient characteristics

Investigators dosed 21 patients as of the data cut-off of October 2.

Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.

All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).

“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”

All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.

Safety

“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”

The investigators observed no dose-limiting toxicities.

Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.

Five (24%) patients experienced neurotoxicity, none grade 3 or higher.

Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.

The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.

The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.

“By day 17, she dramatically improved,” Dr Kochenderfer said.

Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.

On day 30, the patient was out of the intensive care unit.

“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”

Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.

Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.

Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.

Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.

Efficacy

In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.

The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.

The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.

“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”

The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.

The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.

Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.

“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.

However, he noted that the patients are eligible for re-treatment.

Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.

The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.

*Data presented differ from the abstract.

© Phil McCarten 2017

ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).

Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.

In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.

The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.

bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).

BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.

Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).

Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.

Study design

Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.

BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.

The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 10⁶, 150 x 10⁶, 450 x 10⁶, and 800 x 10⁶.

Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.

“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.

Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²).

Patient characteristics

Investigators dosed 21 patients as of the data cut-off of October 2.

Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.

All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).

“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”

All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.

Safety

“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”

The investigators observed no dose-limiting toxicities.

Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.

Five (24%) patients experienced neurotoxicity, none grade 3 or higher.

Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.

The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.

The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.

“By day 17, she dramatically improved,” Dr Kochenderfer said.

Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.

On day 30, the patient was out of the intensive care unit.

“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”

Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.

Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.

Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.

Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.

Efficacy

In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.

The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.

The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.

“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”

The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.

The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.

Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.

“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.

However, he noted that the patients are eligible for re-treatment.

Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.

The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.

*Data presented differ from the abstract.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

For some time, researchers have suspected that diabetes and Alzheimer disease (AD) are similar, but those similarities have been hard to evaluate. Insulin is not needed for glucose to enter the brain or to get into neurons. But NIH researchers may have, for the first time, uncovered a connection.

Using brain tissue samples from participants in the Baltimore Longitudinal Study of Aging, one of the longest-running aging studies, the researchers measured glucose levels in different brain regions, including those either vulnerable or resistant to AD.

The researchers found distinct abnormalities in the way the brain breaks down glucose, and say severity of the abnormalities correlated with the severity of AD pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles in the brains of  patients with AD. More severe reductions in brain glycolysis also were related to symptoms of the disease during life, such as memory problems.

The researchers caution that it is not yet clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of AD symptoms or the speed of disease progression. However, lead investigator Madhav Thambisetty, MD, PhD, says “these findings point to a novel mechanism that could be targeted in the development of new treatments.”

For some time, researchers have suspected that diabetes and Alzheimer disease (AD) are similar, but those similarities have been hard to evaluate. Insulin is not needed for glucose to enter the brain or to get into neurons. But NIH researchers may have, for the first time, uncovered a connection.

Using brain tissue samples from participants in the Baltimore Longitudinal Study of Aging, one of the longest-running aging studies, the researchers measured glucose levels in different brain regions, including those either vulnerable or resistant to AD.

The researchers found distinct abnormalities in the way the brain breaks down glucose, and say severity of the abnormalities correlated with the severity of AD pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles in the brains of  patients with AD. More severe reductions in brain glycolysis also were related to symptoms of the disease during life, such as memory problems.

The researchers caution that it is not yet clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of AD symptoms or the speed of disease progression. However, lead investigator Madhav Thambisetty, MD, PhD, says “these findings point to a novel mechanism that could be targeted in the development of new treatments.”

For some time, researchers have suspected that diabetes and Alzheimer disease (AD) are similar, but those similarities have been hard to evaluate. Insulin is not needed for glucose to enter the brain or to get into neurons. But NIH researchers may have, for the first time, uncovered a connection.

Using brain tissue samples from participants in the Baltimore Longitudinal Study of Aging, one of the longest-running aging studies, the researchers measured glucose levels in different brain regions, including those either vulnerable or resistant to AD.

The researchers found distinct abnormalities in the way the brain breaks down glucose, and say severity of the abnormalities correlated with the severity of AD pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles in the brains of  patients with AD. More severe reductions in brain glycolysis also were related to symptoms of the disease during life, such as memory problems.

The researchers caution that it is not yet clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of AD symptoms or the speed of disease progression. However, lead investigator Madhav Thambisetty, MD, PhD, says “these findings point to a novel mechanism that could be targeted in the development of new treatments.”

For some time, researchers have suspected that diabetes and Alzheimer disease (AD) are similar, but those similarities have been hard to evaluate. Insulin is not needed for glucose to enter the brain or to get into neurons. But NIH researchers may have, for the first time, uncovered a connection.

Using brain tissue samples from participants in the Baltimore Longitudinal Study of Aging, one of the longest-running aging studies, the researchers measured glucose levels in different brain regions, including those either vulnerable or resistant to AD.

The researchers found distinct abnormalities in the way the brain breaks down glucose, and say severity of the abnormalities correlated with the severity of AD pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles in the brains of  patients with AD. More severe reductions in brain glycolysis also were related to symptoms of the disease during life, such as memory problems.

The researchers caution that it is not yet clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of AD symptoms or the speed of disease progression. However, lead investigator Madhav Thambisetty, MD, PhD, says “these findings point to a novel mechanism that could be targeted in the development of new treatments.”

For some time, researchers have suspected that diabetes and Alzheimer disease (AD) are similar, but those similarities have been hard to evaluate. Insulin is not needed for glucose to enter the brain or to get into neurons. But NIH researchers may have, for the first time, uncovered a connection.

Using brain tissue samples from participants in the Baltimore Longitudinal Study of Aging, one of the longest-running aging studies, the researchers measured glucose levels in different brain regions, including those either vulnerable or resistant to AD.

The researchers found distinct abnormalities in the way the brain breaks down glucose, and say severity of the abnormalities correlated with the severity of AD pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles in the brains of  patients with AD. More severe reductions in brain glycolysis also were related to symptoms of the disease during life, such as memory problems.

The researchers caution that it is not yet clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of AD symptoms or the speed of disease progression. However, lead investigator Madhav Thambisetty, MD, PhD, says “these findings point to a novel mechanism that could be targeted in the development of new treatments.”

For some time, researchers have suspected that diabetes and Alzheimer disease (AD) are similar, but those similarities have been hard to evaluate. Insulin is not needed for glucose to enter the brain or to get into neurons. But NIH researchers may have, for the first time, uncovered a connection.

Using brain tissue samples from participants in the Baltimore Longitudinal Study of Aging, one of the longest-running aging studies, the researchers measured glucose levels in different brain regions, including those either vulnerable or resistant to AD.

The researchers found distinct abnormalities in the way the brain breaks down glucose, and say severity of the abnormalities correlated with the severity of AD pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles in the brains of  patients with AD. More severe reductions in brain glycolysis also were related to symptoms of the disease during life, such as memory problems.

The researchers caution that it is not yet clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of AD symptoms or the speed of disease progression. However, lead investigator Madhav Thambisetty, MD, PhD, says “these findings point to a novel mechanism that could be targeted in the development of new treatments.”

Children’s Research Hospital

The US Food and Drug Administration (FDA) has approved a hydroxyurea product (Addmedica’s Siklos) for use in pediatric patients with sickle cell anemia.

Siklos is intended to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients age 2 and older who have sickle cell anemia and recurrent moderate to severe painful crises.

The recommended dose of Siklos is 20 mg/kg once daily.

The FDA granted priority review and orphan drug designation to the application for Siklos.

The agency’s approval of Siklos was based on data from the ESCORT HU study (NCT02516579). The trial was an evaluation of Siklos in 405 patients, ages 2 to 18, with sickle cell disease (SCD).

Thirty-five percent of these patients (n=141) had not received hydroxyurea prior to study enrollment and were therefore evaluable for efficacy. The median follow-up was 23 months (range, 12 to 80 months).

The researchers found that Siklos prompted an increase in fetal hemoglobin. Median fetal hemoglobin percentages were 5.6% (range, 1.3 to 15.0) at baseline and 12.8% (range, 2.1 to 37.2) at around 6 months after Siklos initiation (the value closest to 6 months collected between 5 and 14 months).

In addition, the percentage of patients with at least 1 vaso-occlusive episode, 1 episode of acute chest syndrome, 1 hospitalization due to SCD, or 1 blood transfusion decreased after 12 months of Siklos treatment.

The proportion of patients with at least 1 vaso-occlusive episode was 69.2% at baseline and 42.5% at 12 months. The proportion with at least 1 episode of acute chest syndrome was 23.6% and 5.7%, respectively.

The proportion with at least 1 hospitalization due to SCD was 75.5% and 41.8%, respectively. And the proportion with at least 1 blood transfusion was 45.9% and 23.0%, respectively.

The most common adverse events (occurring in at least 10% of patients) were infections (39.8%), gastrointestinal disorders (13.1%), neutropenia (12.6%), nervous system disorders (11.1%), and metabolic and nutrition disorders (10.9%).

Full prescribing information for Siklos is available on the FDA website.

Children’s Research Hospital

The US Food and Drug Administration (FDA) has approved a hydroxyurea product (Addmedica’s Siklos) for use in pediatric patients with sickle cell anemia.

Siklos is intended to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients age 2 and older who have sickle cell anemia and recurrent moderate to severe painful crises.

The recommended dose of Siklos is 20 mg/kg once daily.

The FDA granted priority review and orphan drug designation to the application for Siklos.

The agency’s approval of Siklos was based on data from the ESCORT HU study (NCT02516579). The trial was an evaluation of Siklos in 405 patients, ages 2 to 18, with sickle cell disease (SCD).

Thirty-five percent of these patients (n=141) had not received hydroxyurea prior to study enrollment and were therefore evaluable for efficacy. The median follow-up was 23 months (range, 12 to 80 months).

The researchers found that Siklos prompted an increase in fetal hemoglobin. Median fetal hemoglobin percentages were 5.6% (range, 1.3 to 15.0) at baseline and 12.8% (range, 2.1 to 37.2) at around 6 months after Siklos initiation (the value closest to 6 months collected between 5 and 14 months).

In addition, the percentage of patients with at least 1 vaso-occlusive episode, 1 episode of acute chest syndrome, 1 hospitalization due to SCD, or 1 blood transfusion decreased after 12 months of Siklos treatment.

The proportion of patients with at least 1 vaso-occlusive episode was 69.2% at baseline and 42.5% at 12 months. The proportion with at least 1 episode of acute chest syndrome was 23.6% and 5.7%, respectively.

The proportion with at least 1 hospitalization due to SCD was 75.5% and 41.8%, respectively. And the proportion with at least 1 blood transfusion was 45.9% and 23.0%, respectively.

The most common adverse events (occurring in at least 10% of patients) were infections (39.8%), gastrointestinal disorders (13.1%), neutropenia (12.6%), nervous system disorders (11.1%), and metabolic and nutrition disorders (10.9%).

Full prescribing information for Siklos is available on the FDA website.

Children’s Research Hospital

The US Food and Drug Administration (FDA) has approved a hydroxyurea product (Addmedica’s Siklos) for use in pediatric patients with sickle cell anemia.

Siklos is intended to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients age 2 and older who have sickle cell anemia and recurrent moderate to severe painful crises.

The recommended dose of Siklos is 20 mg/kg once daily.

The FDA granted priority review and orphan drug designation to the application for Siklos.

The agency’s approval of Siklos was based on data from the ESCORT HU study (NCT02516579). The trial was an evaluation of Siklos in 405 patients, ages 2 to 18, with sickle cell disease (SCD).

Thirty-five percent of these patients (n=141) had not received hydroxyurea prior to study enrollment and were therefore evaluable for efficacy. The median follow-up was 23 months (range, 12 to 80 months).

The researchers found that Siklos prompted an increase in fetal hemoglobin. Median fetal hemoglobin percentages were 5.6% (range, 1.3 to 15.0) at baseline and 12.8% (range, 2.1 to 37.2) at around 6 months after Siklos initiation (the value closest to 6 months collected between 5 and 14 months).

In addition, the percentage of patients with at least 1 vaso-occlusive episode, 1 episode of acute chest syndrome, 1 hospitalization due to SCD, or 1 blood transfusion decreased after 12 months of Siklos treatment.

The proportion of patients with at least 1 vaso-occlusive episode was 69.2% at baseline and 42.5% at 12 months. The proportion with at least 1 episode of acute chest syndrome was 23.6% and 5.7%, respectively.

The proportion with at least 1 hospitalization due to SCD was 75.5% and 41.8%, respectively. And the proportion with at least 1 blood transfusion was 45.9% and 23.0%, respectively.

The most common adverse events (occurring in at least 10% of patients) were infections (39.8%), gastrointestinal disorders (13.1%), neutropenia (12.6%), nervous system disorders (11.1%), and metabolic and nutrition disorders (10.9%).

Full prescribing information for Siklos is available on the FDA website.

Image by Difu Wu

The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.

Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.

Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.

Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.

Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.

After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.

BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.

If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.

BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.

The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.

ENESTfreedom

This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.

Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).

Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.

Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.

ENESTop

This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.

At 96 weeks, 53.2% of patients were still in TFR.

Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.

As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.

Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.

Image by Difu Wu

The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.

Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.

Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.

Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.

Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.

After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.

BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.

If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.

BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.

The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.

ENESTfreedom

This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.

Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).

Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.

Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.

ENESTop

This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.

At 96 weeks, 53.2% of patients were still in TFR.

Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.

As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.

Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.

Image by Difu Wu

The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.

Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.

Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.

Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.

Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.

After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.

BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.

If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.

BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.

The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.

ENESTfreedom

This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.

Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).

Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.

Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.

ENESTop

This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.

At 96 weeks, 53.2% of patients were still in TFR.

Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.

As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.

Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.

Clinical question: What are the effects of isolation precautions on hospital outcomes and cost of care?

Background: Previous studies have found that isolation precautions negatively affect various aspects of patient care, including frequency of contact with clinicians, adverse events in the hospital, measures of patient well-being, and patient experience scores. It is not known how isolation precautions affect other hospital-based metrics, such as 30-day readmissions, length of stay (LOS), in-hospital mortality, and cost of care.

Study design: Multisite, retrospective, propensity score–matched cohort study.

Setting: Three academic tertiary care hospitals in Toronto.

Synopsis: The authors used administrative databases and propensity-score modeling to match isolated patients and nonisolated controls. Researchers included 17,649 control patients, 737 patients isolated for methicillin-resistant Staphylococcus aureus (contact isolation), and 1,502 patients isolated for respiratory illnesses (contact and droplet isolation) in the study. Patients isolated for MRSA had a higher 30-day readmission rate than did controls (19% vs. 14.7%), a longer average length of stay (11.9 days vs. 9.1 days), and higher direct costs ($11,009 vs. $7,670). Patients isolated for respiratory illnesses had a longer average length of stay (8.5 days vs. 7.6 days) and higher direct costs ($7,194 vs. $6,294). No differences in adverse events rates or in-hospital mortality were observed between control patients and patients in either isolation group.

Some of the differences observed may be from illness severity rather than from the effects of isolation, especially in the MRSA group. There was no difference observed in rates of adverse outcomes, such as falls or medication errors, or in rates of formal patient complaints to the hospital. It is possible that propensity score modeling corrected for unidentified biases in prior studies that found differences in these types of outcomes.

Bottom line: Isolation precautions are associated with higher costs and longer LOS in hospitalized general medicine patients.

Citation: Tran K et al. The effect of hospital isolation precautions on patient outcomes and cost of care: A multisite, retrospective, propensity score-matched cohort study. J Gen Intern Med. 2017;32(3):262-8.

Dr. Wachter is an assistant professor of medicine at Duke University.

Clinical question: What are the effects of isolation precautions on hospital outcomes and cost of care?

Background: Previous studies have found that isolation precautions negatively affect various aspects of patient care, including frequency of contact with clinicians, adverse events in the hospital, measures of patient well-being, and patient experience scores. It is not known how isolation precautions affect other hospital-based metrics, such as 30-day readmissions, length of stay (LOS), in-hospital mortality, and cost of care.

Study design: Multisite, retrospective, propensity score–matched cohort study.

Setting: Three academic tertiary care hospitals in Toronto.

Synopsis: The authors used administrative databases and propensity-score modeling to match isolated patients and nonisolated controls. Researchers included 17,649 control patients, 737 patients isolated for methicillin-resistant Staphylococcus aureus (contact isolation), and 1,502 patients isolated for respiratory illnesses (contact and droplet isolation) in the study. Patients isolated for MRSA had a higher 30-day readmission rate than did controls (19% vs. 14.7%), a longer average length of stay (11.9 days vs. 9.1 days), and higher direct costs ($11,009 vs. $7,670). Patients isolated for respiratory illnesses had a longer average length of stay (8.5 days vs. 7.6 days) and higher direct costs ($7,194 vs. $6,294). No differences in adverse events rates or in-hospital mortality were observed between control patients and patients in either isolation group.

Some of the differences observed may be from illness severity rather than from the effects of isolation, especially in the MRSA group. There was no difference observed in rates of adverse outcomes, such as falls or medication errors, or in rates of formal patient complaints to the hospital. It is possible that propensity score modeling corrected for unidentified biases in prior studies that found differences in these types of outcomes.

Bottom line: Isolation precautions are associated with higher costs and longer LOS in hospitalized general medicine patients.

Citation: Tran K et al. The effect of hospital isolation precautions on patient outcomes and cost of care: A multisite, retrospective, propensity score-matched cohort study. J Gen Intern Med. 2017;32(3):262-8.

Dr. Wachter is an assistant professor of medicine at Duke University.

Clinical question: What are the effects of isolation precautions on hospital outcomes and cost of care?

Background: Previous studies have found that isolation precautions negatively affect various aspects of patient care, including frequency of contact with clinicians, adverse events in the hospital, measures of patient well-being, and patient experience scores. It is not known how isolation precautions affect other hospital-based metrics, such as 30-day readmissions, length of stay (LOS), in-hospital mortality, and cost of care.

Study design: Multisite, retrospective, propensity score–matched cohort study.

Setting: Three academic tertiary care hospitals in Toronto.

Synopsis: The authors used administrative databases and propensity-score modeling to match isolated patients and nonisolated controls. Researchers included 17,649 control patients, 737 patients isolated for methicillin-resistant Staphylococcus aureus (contact isolation), and 1,502 patients isolated for respiratory illnesses (contact and droplet isolation) in the study. Patients isolated for MRSA had a higher 30-day readmission rate than did controls (19% vs. 14.7%), a longer average length of stay (11.9 days vs. 9.1 days), and higher direct costs ($11,009 vs. $7,670). Patients isolated for respiratory illnesses had a longer average length of stay (8.5 days vs. 7.6 days) and higher direct costs ($7,194 vs. $6,294). No differences in adverse events rates or in-hospital mortality were observed between control patients and patients in either isolation group.

Some of the differences observed may be from illness severity rather than from the effects of isolation, especially in the MRSA group. There was no difference observed in rates of adverse outcomes, such as falls or medication errors, or in rates of formal patient complaints to the hospital. It is possible that propensity score modeling corrected for unidentified biases in prior studies that found differences in these types of outcomes.

Bottom line: Isolation precautions are associated with higher costs and longer LOS in hospitalized general medicine patients.

Citation: Tran K et al. The effect of hospital isolation precautions on patient outcomes and cost of care: A multisite, retrospective, propensity score-matched cohort study. J Gen Intern Med. 2017;32(3):262-8.

Dr. Wachter is an assistant professor of medicine at Duke University.

Despite the justified concern about rising opiate use in the United States, cannabis remains the most commonly used substance in the 12- to 17-year-old population.¹ Cannabis use is widespread, particularly in states in which it has been decriminalized or legalized. While use of alcohol and nicotine has fallen among high school students from the years 2010 to 2015, marijuana use has remained relatively constant.² In addition, the potency of cannabis with regard to tetrahydrocannabinol (THC) content has increased over the years. Despite the common belief among the public that cannabis use is benign, accumulating research is revealing a number of concerning consequences, especially in vulnerable populations and those who use cannabis regularly.

Case summary

petdcat/Thinkstock

Case discussion

Treatment for these adverse effects of cannabis is cessation of the drug. This can be accomplished through hard work with a counselor, who may recommend any of a number of treatments, including contingency management, cognitive behavioral therapy, systematic multidimensional family therapy, and motivational enhancement therapy, among others.⁵ While common lore is that it is impossible to stop cannabis use, the effect sizes of these treatments is in the moderate to large range. There are viable options to stop cannabis use, especially when it becomes problematic.
 

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Email him at [email protected].

References

1. “Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings,” Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality, 2013.

2. “Monitoring the Future Survey, 2015,” National Institute on Drug Abuse.

3. Pharmaceuticals (Basel). 2012 Jul;5(7):719-26.

4. Nat Rev Neurosci. 2007 Nov;8(11):885-95.

5. Dtsch Arztebl Int. 2016 Sep;113(39): 653-9.

Despite the justified concern about rising opiate use in the United States, cannabis remains the most commonly used substance in the 12- to 17-year-old population.¹ Cannabis use is widespread, particularly in states in which it has been decriminalized or legalized. While use of alcohol and nicotine has fallen among high school students from the years 2010 to 2015, marijuana use has remained relatively constant.² In addition, the potency of cannabis with regard to tetrahydrocannabinol (THC) content has increased over the years. Despite the common belief among the public that cannabis use is benign, accumulating research is revealing a number of concerning consequences, especially in vulnerable populations and those who use cannabis regularly.

Case summary

petdcat/Thinkstock

Case discussion

Treatment for these adverse effects of cannabis is cessation of the drug. This can be accomplished through hard work with a counselor, who may recommend any of a number of treatments, including contingency management, cognitive behavioral therapy, systematic multidimensional family therapy, and motivational enhancement therapy, among others.⁵ While common lore is that it is impossible to stop cannabis use, the effect sizes of these treatments is in the moderate to large range. There are viable options to stop cannabis use, especially when it becomes problematic.
 

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Email him at [email protected].

References

1. “Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings,” Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality, 2013.

2. “Monitoring the Future Survey, 2015,” National Institute on Drug Abuse.

3. Pharmaceuticals (Basel). 2012 Jul;5(7):719-26.

4. Nat Rev Neurosci. 2007 Nov;8(11):885-95.

5. Dtsch Arztebl Int. 2016 Sep;113(39): 653-9.

Despite the justified concern about rising opiate use in the United States, cannabis remains the most commonly used substance in the 12- to 17-year-old population.¹ Cannabis use is widespread, particularly in states in which it has been decriminalized or legalized. While use of alcohol and nicotine has fallen among high school students from the years 2010 to 2015, marijuana use has remained relatively constant.² In addition, the potency of cannabis with regard to tetrahydrocannabinol (THC) content has increased over the years. Despite the common belief among the public that cannabis use is benign, accumulating research is revealing a number of concerning consequences, especially in vulnerable populations and those who use cannabis regularly.

Case summary

petdcat/Thinkstock

Case discussion

Treatment for these adverse effects of cannabis is cessation of the drug. This can be accomplished through hard work with a counselor, who may recommend any of a number of treatments, including contingency management, cognitive behavioral therapy, systematic multidimensional family therapy, and motivational enhancement therapy, among others.⁵ While common lore is that it is impossible to stop cannabis use, the effect sizes of these treatments is in the moderate to large range. There are viable options to stop cannabis use, especially when it becomes problematic.
 

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Email him at [email protected].

References

1. “Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings,” Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality, 2013.

2. “Monitoring the Future Survey, 2015,” National Institute on Drug Abuse.

3. Pharmaceuticals (Basel). 2012 Jul;5(7):719-26.

4. Nat Rev Neurosci. 2007 Nov;8(11):885-95.

5. Dtsch Arztebl Int. 2016 Sep;113(39): 653-9.