A Biobehavioral Perspective on Caring for Allogeneic Hematopoietic Stem Cell Transplant Survivors with Graft-Versus-Host Disease

Abstract

Among the potential complications of allogeneic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) is common and associated with significant physical and psychosocial symptom burden. Despite substantial advances in GVHD treatment, the global immune suppression that frequently accompanies GVHD treatment also contributes to high rates of physical and emotional suffering and mortality. The complex manifestations of GVHD and its treatment warrant a multidisciplinary team-based approach to managing patients’ multi-organ system comorbidities. A biobehavioral framework can enhance our understanding of the complex association between medications, physical symptoms, and psychosocial distress in patients with GVHD. Hence, for this perspective, we highlight the importance of addressing both the physical and psychosocial needs experienced by patients with GVHD and provide guidance on how to approach and manage those symptoms and concerns as part of comprehensive cancer care.

INTRODUCTION

Whether acute or chronic, GVHD is associated with worse physical functioning, general health, emotional well-being, social and role functioning, and global quality of life (QOL) [1–7]. GVHD complications and treatment cause long-term morbidity which compromises patients’ QOL [8]. The financial toxicity associated with chronic GVHD also jeopardizes well-being and QOL, with the annual cost of GVHD for a commercially insured patient estimated at $291,357 per year [9]. However, there is limited data on evidence-based approaches to holistically address the complex psychosocial and physical needs of HSCT survivors living with GVHD across the lifespan. Therefore, we describe here the biobehavioral considerations for GVHD and provide an overview of psychosocially informed clinical approaches to address these needs.

BIOBEHAVIORAL CONSIDERATIONS

A biobehavioral framework, defined as the interaction between behavioral, psychological, socioenvironmental, and biological processes, is useful for addressing the physical and emotional health needs of HSCT survivors living with chronic GVHD [10]. A biobehavioral approach is particularly relevant to patients with GVHD given its accompanying complex physiological processes including the critical role of the immune response and the dynamic interconnections between mental and physical health. This framework also provides insights into environmental influences affecting patients’ responses to treatment [10–13].

Emerging biobehavioral evidence continues to support a relationship between psychological state and GVHD symptoms [12,14,15]. For instance, pre-HSCT depression is associated with higher incidence of acute GVHD [16]. Proposed mechanisms include the activation of the hypothalamic-pituitary-adrenal (HPA) and sympathetic nervous system (SNS) axes by psychosocial stressors and patterns of health behaviors, with concurrent activation of proteomic, genomic, and metabolomic pathways implicated in GVHD. Neurotransmitters (eg, catecholamines), steroid hormones (eg, glucocorticoids), and direct sympathetic innervation of the bone marrow microenvironment can modulate cell recovery following HSCT and promote a proinflammatory environment that predisposes the HSCT survivor to GVHD and other HSCT-associated complications [11,12]. Cytokines and proinflammatory states may also contribute to severe chronic GVHD, cognitive symptoms, pain, fatigue, sleep disruption, sexual dysfunction, and psychiatric symptoms (eg, depression and anxiety) [11,12]. Tailored biobehavioral interventions for HSCT survivors with GVHD may improve the QOL and overall well-being of these patients. Further, application of psychoneuroimmunology- and genomics-based investigations can help researchers better understand how psychosocial interventions (eg, cognitive-behavioral approaches, mindfulness-based therapy, and physical activity) can manage physical and psychiatric symptoms, and contribute to more favorable transcriptome profiles such as decreased pro-inflammatory gene expression [10,11,17,18].

A biobehavioral framework can also enhance our understanding of the complex association between medications, physical symptoms, and psychosocial distress in patients with GVHD. Physiologically stressed states such as depression and GVHD, coupled with increased SNS activity, can lead to increased ß-adrenergic receptor activation, which stimulates inflammatory reactions [19]. A recent study in patients who underwent allogeneic HSCT showed a trend in the association between use of the ß-adrenergic receptor antagonist propranolol and reduced risk of developing chronic GVHD [20]. Additionally, certain psychotropic agents routinely used for depression, vilazodone and bupropion, have anti-inflammatory effects that may be of particular use in pro-inflammatory conditions, such as GVHD [21,22]. While the interleukin-6 blocking agent tocilizumab used for GVHD prevention was hypothesized to improve psychosocial symptoms, it was unexpectedly found to be associated with an increase in depressive symptoms, anxiety, pain, and sleep difficulties among allogeneic HSCT survivors [14]. These results highlight the complexity of directionality in the relationship between the inflammatory response in GVHD and psychosocial distress, and emphasize the need for more research in this area. The adverse effects of stress-related biobehavioral processes may also impact immune recovery and function and are particularly salient for HSCT recipients with GVHD, given the importance of inflammation in the trajectory of GVHD. Therefore, adopting a biobehavioral research framework to explore the intersection between behavior, psychology, socioenvironmental factors, and biological processes in individuals living with GVHD presents immense potential in advancing treatment and other interventions to improve outcomes for these patients.

PSYCHOLOGICAL DISTRESS SYMPTOMS AND MANAGEMENT

The physical, emotional, and psychological impacts of GVHD can decrease QOL in HSCT survivors [7]. The complexities of GVHD, including ongoing medical treatments, symptom management, and anticipation of potential complications, can be disruptive to life roles and contribute to the development or exacerbation of psychiatric symptoms. Please refer to Table 1 for a summary of management strategies.

Table 1.

Summary of Management Strategies for Psychological Distress

Psychological Distress Symptoms	Management Considerations
Anxiety and depression	Cognitive-behavioral interventions Pharmacologic agents (eg, antidepressants, antipsychotics, benzodiazepines)
Post-traumatic stress	Cognitive-behavioral interventions (eg, image rehearsal therapy) Pharmacologic agents (eg, prazosin)
Demoralization	Evaluate for psychiatric illness Treat physical symptoms that may be triggering distress Allow patients to share their experiences of illness Help patients to define priorities and values Consider referral to spiritual care
Sleep disruption/insomnia	Cognitive-behavioral therapy for insomnia Aromatherapy Music therapy Massage therapy Pharmacologic agents (eg, benzodiazepines, doxylamine, lemborexant) Treat restless leg syndrome with pharmacologic agents (eg, dopamine agonists, pregabalin)
Fatigue	Treat and rule out underlying medical causes Physical activity Pharmacologic agents (eg, psychostimulants, modafinil)
Sexual health problems	Initiate conversations about sexual health concerns Provide education, normalization, and empowerment about sexual health concerns Individualize symptom management Coordinate with gynecologic care providers
Pain	Treat underlying causes Physical therapy Relaxation techniques Cognitive-behavioral and acceptance-based approaches Pharmacologic agents (eg, neuropathic pain medications)
Cognitive impairment	Manage treatment-related complications Optimize sleep Cognitive rehabilitation and training Physical activity Pharmacologic agents (eg, modafinil, methylphenidate, gingko biloba)
Corticosteroid-related psychiatric symptoms	Avoid abrupt discontinuation of corticosteroids For mood symptoms consider antipsychotic or mood stabilizer
Existential distress and spiritual well-being	Dignity therapy Meaning-centered psychotherapy Consider referral to spiritual care

Anxiety and Depression Symptoms

Overview:

Among patients living with chronic GVHD, 50% and 30% report symptoms of depression and anxiety, respectively [23]. Moreover, the incidence of GVHD is reported to be higher among patients who died by suicide after allogeneic HSCT [24]. Higher symptom burden, worse functional status, and greater use of negative emotionoriented coping are associated with worse anxiety, depression, and QOL [23,25]. Evidence suggests that moderate and severe chronic GVHD are linked with worse anxiety and depression symptoms, respectively [26]. HSCT survivors with chronic GVHD affecting the skin or GI tract had more severe depression than HSCT survivors without chronic GVHD [26].

Management:

Management of anxiety and depression symptoms includes nonpharmacological and pharmacological strategies.

Nonpharmacologic strategies:

Since coping mediates the relationship between psychological distress and QOL [7,23], supportive interventions that enhance adaptive coping skills may reduce the burden of psychological distress and improve QOL among patients with GVHD [27,28]. Although not specifically studied in patients living with GVHD, psychosocial interventions such as cognitive-behavioral therapy for treating depression and anxiety have demonstrated efficacy in cancer survivors [29]. Furthermore, in a study of post-HSCT patients, those who completed a cognitive-behavioral intervention reported fewer depressive symptoms [30].

Pharmacologic strategies:

Although no clinical trials have established the efficacy of pharmacologic treatments for depression and anxiety in HSCT patient populations, several classes of psychotropic medications including antidepressants, benzodiazepines, and antipsychotic medications are commonly used [31,32]. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors are routinely used to treat depression and anxiety symptoms [33]. However, almost all classes of antidepressants have been reported to affect hemostasis [34]. The depletion of platelet serotonin and reduced platelet aggregation is implicated in bleeding associated with SSRI use [35,36]. Additionally, SSRIs increase gastric acidity, which can increase the risk of ulcer formation and gastrointestinal bleeding [37]. Further, antidepressants with high serotonin transporter binding affinity (eg, sertraline) place patients at a higher bleeding risk than intermediate (eg, imipramine) and low (eg, bupropion) binding affinity agents [38]. Of note, mirtazapine, a tetracyclic antidepressant commonly used to target somatic symptoms (eg, insomnia, poor appetite) that may accompany depression and anxiety symptoms, can cause agranulocytosis in a small percentage of patients [39].

Benzodiazepines can be used to manage anxiety either on an as-needed basis or for a short period of time in the setting of acute anxiety [40]. However, like other sedative-hypnotic drugs, benzodiazepines can interfere with memory [41], though usually in a mild and dose-dependent fashion. Typically, short half-life benzodiazepines (eg, lorazepam) are used at low doses and, if clinically possible, for brief periods of time [42]. Antipsychotics (eg, quetiapine, olanzapine, haloperidol) have anxiolytic [43], antiemetic (eg, haloperidol, olanzapine) [44], and appetite stimulant (olanzapine) [45] properties. However, antipsychotics should be used with caution due to the risk of neutropenia and agranulocytosis [46].

Post-Traumatic Stress

Overview:

Multiple aspects of the transplantation process can be traumatic for patients undergoing HSCT [47]. Unfortunately, traumatic stress symptoms can persist beyond the transplant hospitalization into short- and long-term recovery [48,49]. Overall, 5% to 9% of HSCT survivors develop illness-related symptoms of post-traumatic stress disorder (PTSD) [50]. Factors associated with PTSD include pre-existing psychological distress, limited social support, financial difficulties, tendency to use avoidance-based coping strategies, and disease burden [49,51]. Longer hospital length of stay also predicts PTSD symptom severity [52]. Although the chronicity of GVHD does not appear to affect the severity of PTSD symptoms, having both acute and chronic GVHD is associated with worse PTSD symptoms [53,54]. Post-HSCT patients with PTSD symptoms self-reported significantly higher fatigue and worse QOL than those without PTSD symptoms [55].

Management:

The management of PTSD symptoms among patients living with GVHD has not been specifically studied in clinical trials; however, post-HSCT patients, a small subset of whom had previously been diagnosed with GVHD, who participated in a 10-session cognitive-behavioral intervention had fewer PTSD symptoms, including intrusive thoughts and avoidance, compared to an assessment-only control [30]. Moreover, greater personal resilience levels in post-HSCT patients have been correlated with greater decreases in PTSD symptoms [56]. Further research is needed to identify whether interventions that specifically bolster resiliency can reduce PTSD symptoms. For management of trauma-related nightmares, the selective alpha-1 adrenergic antagonist prazosin and a cognitive-behavioral intervention, image rehearsal therapy, have both been shown to be efficacious in a recent network meta-analysis [57]. Further, the use of prazosin along with psychosocial support to rapidly improve healthcareassociated nightmares has been described in the outpatient palliative care setting [58]. For patients struggling with nightmares related to their experiences with GVHD, a combination of psychosocial interventions and prazosin may reduce unwanted SNS activity and symptoms.

Demoralization

Overview:

Demoralization syndrome is a disorder of adjustment or failure to cope that is characterized by feelings of helplessness, hopelessness, worthlessness, and meaninglessness in life [59]. A recent study of end-of-life cancer patients with a life expectancy of 4 months or less undergoing palliative care demonstrated that demoralization is associated with worse QOL in all domains: physical, social, emotional, and functional well-being [60]. Demoralization can be present in patients at any stage of the HSCT trajectory [61]. The symptoms of demoralization syndrome are similar to those of depression, including low mood, loss of interest in activities, loss of selfesteem, and feelings of guilt. However, unlike depression, demoralization syndrome does not have persistent low mood and loss of pleasure. Patients experiencing demoralization may have fluctuations in their mood and can feel pleasure when the stressor is no longer present. Acutely demoralized patients may experience existential distress, which can exacerbate physical and psychological symptoms [62].

Management:

Recognizing and addressing demoralization in patients with GVHD is important, given that high levels of demoralization have been noted to be an independent risk factor for suicidal ideation [63]. Evaluation for psychiatric illness is an important initial step when patients exhibit signs of demoralization. Identifying and treating any underlying physical symptoms that could be triggering existential distress may help resolve acute symptoms of hopelessness and improve existential well-being [64]. Helpful strategies include connecting with the patient as a human being, taking a narrative history (eg, the provider allowing the patient to share their experience of illness in relation to their life trajectory), analyzing with the patient why stressors feel so threatening, and raising awareness of any distorted perceptions [62]. While spiritual care providers can be invaluable in this process, patients may decline referral to spiritual care. To move beyond demoralization into a state of resilience, strategies include helping the patient to recall sources of strength and support they have used when dealing with past experiences of helplessness and hopelessness, creating a sense of meaning from their current experience, formulating a course of action, defining priorities and values, and supporting the patient to live in alignment with their core values [62]. Offering the patient opportunities to describe their core values and functional goals may help the clinician to prioritize treatment approaches.

Sleep Disruption/Insomnia

Overview:

Patients may develop sleep disturbances due to corticosteroid treatment for chronic GVHD, inflammation due to chronic GVHD or infection, uncertainty or fear of disease progression, pain, or additional treatments for relapsed disease [65]. In a recent study of adults with chronic GVHD, 54% had clinically significant insomnia symptoms [26]. Long-term use of steroids for the treatment of chronic GVHD is a risk factor for obstructive sleep apnea due to weight gain [66]. Muscle cramps and neuropathy due to medications commonly used by patients with GVHD can also disrupt sleep [67]. Neuropathy is also a risk factor for restless leg syndrome (ie, an urge to move the legs during rest with relief upon movement that is worse or occurs only in the evening or night) [68], which can further exacerbate sleep disturbances. The prevalence of restless leg syndrome was 18% among patients with cancer treated with standard-dose chemotherapy [69].

Management:

Treatments for sleep disruption in patients with GVHD depend on the underlying cause. Sleep disruption can be managed with a combination of nonpharmacological interventions and pharmacotherapy.

Nonpharmacologic strategies:

Interventions that have shown efficacy in improving sleep include aromatherapy, music, and massage [70–72]. Brief behavioral treatments for insomnia can be delivered by providers without specialized training. Cognitive-behavioral therapy for insomnia is a first-line treatment for chronic insomnia [73].

Pharmacologic strategies:

Acute sleep disturbances can be treated with benzodiazepines, doxylamine, eszopiclone, lemborexant, zolpidem, and zopiclone [74]. Considering the high risk of delirium in the HSCT population [59], the risks and benefits of deliriogenic agents such as benzodiazepines should be carefully considered. Antidepressants effective for chronic insomnia include doxepin and trazodone [75]. First-line treatment for restless leg syndrome includes dopamine agonists such as pramipexole and ropinirole [76]. Other classes of medications commonly used to manage restless leg syndrome include levodopa with a dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, cabergoline, and benzodiazepine receptor agonists [77–79]. Although studies describing treatment options for restless leg syndrome in the HSCT population are limited, pregabalin shows promise for treating restless leg syndrome secondary to neuropathy and/or neuropathic pain [80]. Antidepressant (eg, citalopram, paroxetine, amitriptyline, mirtazapine) use is a risk factor for restless leg syndrome, although evidence is mixed [76]. Thus, avoidance or discontinuation of use of these medications should be considered in patients with restless leg syndrome.

Fatigue

Overview:

Fatigue is the most common symptom experienced after allogeneic HSCT and is often pervasive and debilitating among those living with GVHD [81,82]. The prevalence of clinically significant fatigue was 68% among adults with chronic GVHD [26]. The immune dysregulation from GVHD not only impairs recovery post-HSCT but also contributes to overwhelming fatigue [81,82]. The causes of fatigue in patients with GVHD are multifactorial, stemming from chronic inflammation, insomnia, organ damage, pain, and complications such as infections or medication adverse effects [83]. This relentless fatigue significantly diminishes patients’ QOL, making even routine activities challenging [84,85].

Management:

The first step is evaluation to treat and rule out underlying medical causes before using other supportive care approaches. GVHD-related fatigue management necessitates a multidisciplinary approach that includes symptom management, psychosocial support, and interventions tailored to the patient’s unique needs. However, data on GVHD-related fatigue management for the HSCT population is limited.

Nonpharmacologic strategies:

Greater GVHD symptoms and physical inactivity are independently associated with fatigue [84] and may be potentially modifiable targets for future clinical and behavioral interventions designed to reduce fatigue in this population.

Pharmacologic strategies:

Drawing from evidence in the general oncology population [86], psychostimulants (eg, methylphenidate) may be moderately effective in reducing cancer-related fatigue; however, an increased risk of sleep problems and decreased appetite must be weighed against potential benefits [87,88]. Modafinil, a wakefulness-promoting agent, is also used to manage cancer-related fatigue [89]. Of note, because modafinil can induce CYP3A4 activity, coadministration of modafinil with tacrolimus (metabolized by CYP3A) may result in decreased tacrolimus trough concentrations and increase the risk of organ rejection [90–92]. Modafinil or armodafinil were not found to improve fatigue in a recent systematic review and meta-analysis [88]. Erythropoietin had a small effect size in reducing fatigue that was not clinically significant, suggesting that it should not be routinely used for the treatment of fatigue [88]. More research is needed on pharmacologic approaches to ameliorate fatigue in patients with GVHD.

Sexual Health Problems

Overview:

Patients with chronic GVHD have sexual function below the normative population mean, with 58% of patients in the low sexual function range [26]. The causes of sexual problems in patients with GVHD are multifactorial. The HSCT conditioning regimen (eg, chemotherapy and radiotherapy) pretransplant, medications for GVHD, and GVHD are associated with short- and long-term effects including physical changes (eg, vulvovaginal GVHD) and sexual dysfunction [3,93,94]. Sexual dysfunction is characterized by the difficulty experienced by an individual or a couple during any stage of sexual activity, including physical pleasure, desire, preferences, arousal, and orgasm [93,95]. Genital chronic GVHD, characterized by vulvovaginal symptoms (eg, dryness, pruritis, pain, dyspareunia, bleeding) can lead to severe complications such as vaginal stenosis and scar tissue formation [3]. Males can experience increased sensitivity in the skin around the penis [3]. The incidence of genital chronic GVHD in allogeneic HSCT recipients is 35% to 52% in women [96,97] and 20% in men [98]. Sexual function in female survivors of allogeneic HSCT may be negatively affected by GVHD due to fatigue, mucositis in the genital tract, and vulvovaginal atrophy [95]. After HSCT, more than 90% of women experience primary ovarian insufficiency [99,100]. In HSCT survivors, hypogonadism and infertility are associated with worse QOL [101,102].

Management:

Many factors contribute to healthy sexual function, including mental and physical health, self-esteem, and relationships [95]. Given the impact of GVHD on physical and psychological symptoms, individualized symptom management is an important first step. Patients may expect their providers to initiate conversations about sexual health concerns [103]. Thus, designating a member of the transplant team to assess for sexual health concerns can help ensure that these discussions occur. Care of female HSCT recipients may require coordination with gynecologic care providers [104]. The vulvovaginal symptoms of genital GVHD may also suggest primary ovarian insufficiency, which warrants referral to a gynecologic provider [104]. Feasibility for both male and female HSCT survivors was demonstrated in a multimodal intervention involving monthly visits with clinicians who (1) assessed the causes of sexual dysfunction, (2) provided education, normalization, and empowerment to the patient regarding sexual health concerns, and (3) delivered therapeutic interventions targeting specific sexual health needs (eg, psychoeducation or topical treatment for GVHD) [105]. A proactive and inquisitive approach to patients’ sexual health needs may lead to earlier identification and treatment of modifiable causes of sexual health concerns.

Pain

Overview:

Patients with severe chronic GVHD have reported significantly worse pain intensity compared to patients who had undergone allogeneic HSCT without chronic GVHD [26]. The immune-mediated process in GVHD can cause various types of pain, which can significantly impact the patient’s QOL [106]. Pain in patients with GVHD has multiple causes, including the activation of immune cells and subsequent release of autoantibodies and cytokines, chemotherapy, radiotherapy, and GVHD treatments [107]. Examples of pain related to involvement of organ systems in chronic GVHD include painful skin erosions, mucosal oral cavity lesions, ocular inflammation, vaginal dyspareunia [108], and muscle pain [107]. Calcineurin inhibitors (eg, tacrolimus, cyclosporine) are mainstays of treatment for GVHD, but can be associated with calcineurin inhibitor-induced pain syndrome, thought to be mediated by the interruption of the calcineurin signaling pathway [109].

Management:

Targeted pain management in patients with GVHD is crucial to improving the patient’s overall well-being. Poorly managed pain can exacerbate psychological symptoms and undermine QOL [110]. Treatment involves identifying the underlying causes and utilizing a combination of pharmacological interventions (eg, neuropathic pain medications) and nonpharmacological approaches such as physical therapy, relaxation techniques, and cognitive-behavioral and acceptance-based approaches to address any behavioral and psychological aspects of pain. For pain caused by the immune activation in GVHD, immunomodulatory therapy such as corticosteroids or ruxolitinib may be necessary [111]. Treatment of calcineurin inhibitor-induced pain syndrome involves calcineurin inhibitor discontinuation, dose reduction, or replacement with another calcineurin inhibitor. Careful monitoring is needed as reduction in calcineurin inhibitor concentration may worsen GVHD. Use of pregabalin may also reduce symptoms from calcineurin inhibitor-induced pain syndrome [112].

Each patient with GVHD may experience pain differently. A patient-centered approach that considers the patient’s specific pain experience is essential. Communication between the patient and healthcare team is vital to tailor pain management strategies effectively.

Cognitive Impairment

Overview:

Individuals with GVHD experience cognitive deficits, demonstrating worse performance on working memory tasks compared to those without GVHD [113]. Patients with chronic GVHD had similar cognitive function compared to the population mean, but 22% of patients had scores indicative of mild cognitive impairment [26]. The causes of cognitive impairment in the GVHD population are also multifactorial. While central nervous system GVHD can directly cause cognitive impairment characterized by diverse neurological symptoms such as delirium, ataxia, motor deficits, seizures, optic neuritis, and myelitis [114–119], central nervous system GVHD is rare. Common causes of cognitive impairment in patients with GVHD include neurotoxicity from GVHD prophylaxis medications, such as immunosuppressants like cyclosporine and tacrolimus. These medications are known to have neurotoxic effects including insomnia, psychosis, catatonia, delusions, mania, tremor, thrombotic microangiopathy, and posterior reversible encephalopathy syndrome [120–123]. Other causes of cognitive impairment in individuals with GVHD may include prior intensive chemotherapy, allogeneic HSCT, conditioning regimen, and total brain irradiation [124,125]. Among survivors of HSCT (36% allogeneic HSCT) in the Netherlands compared to an age-, sex-, and education level-matched reference group, there was a higher prevalence of cognitive dysfunction (34.8% versus 21.3%) with worse scores for memory, information processing speed, executive function, and attention [126].

Management:

Management of cognitive impairment in GVHD patients involves addressing the underlying causes, such as controlling the GVHD itself through immunosuppressive therapy, managing any treatment-related complications, optimizing sleep, and providing supportive care. Additionally, cognitive rehabilitation and psychological support can help patients cope with and improve cognitive deficits. Exercise interventions have demonstrated benefits for cancer-related cognitive impairment, with effects primarily on self-reported outcomes [127]. Among cancer survivors in general, however, it appears that cognitive symptoms and neuropsychological test scores may improve with time [128]. Behavioral interventions such as cognitive training have shown improvements in self-reported cognitive symptoms compared to a control group, but without significant improvements on neuropsychological testing [129]. There is currently no evidence to support the use of pharmacological agents for the treatment of cognitive impairment in GVHD patients. However, there is some evidence supporting the use of pharmacological agents for cognitive impairment in cancer therapy-induced cognitive symptoms (eg, modafinil, methylphenidate, ginkgo biloba) [130]. More research is warranted to investigate the efficacy of these pharmacological treatments for cognitive impairment in patients with GVHD.

Psychiatric Sequalae of Corticosteroids

Overview:

Corticosteroids are an important tool in modulating the immune response in acute or chronic GVHD, and can effectively manage various symptoms [131]. However, steroids increase the risk for mood disorders (eg, hypomania, mania, mixed states, depression), anxiety and panic disorder, delirium, suicidal thinking and behavior in the context of affective syndromes or delirium, aggressive behavior, paranoia, insomnia, and depersonalization [132–135]. Hyperactivity of the HPA axis (ie, elevated levels of cortisol and adrenocorticotropic hormone) has been associated with major depressive disorder [136], suggesting that exogenous corticosteroid use may disrupt the HPA axis and place individuals at higher risk for developing mood disorders. In patients with cancer, high-dose corticosteroid treatment was associated with a 5% to 10% incidence of major psychiatric symptoms [137]. Steroid use has also been associated with cognitive impairments (eg, impaired attention, concentration, episodic memory, and word-finding) that may not completely resolve even several years after steroid discontinuation [135].

Management:

Clinical trials on effective treatment of psychiatric sequelae of steroids in patients with GVHD are limited. Steroid dose reduction or discontinuation should always be considered with close monitoring. High doses and/or prolonged courses of steroids should not be discontinued abruptly, given the risk for developing psychotic or mood-related symptoms [138]. Corticosteroid-induced hypomania, mania, and mixed mania have been successfully treated with an antipsychotic or mood stabilizer, most often haloperidol [139], haloperidol with lithium [140], risperidone [141], quetiapine [142], olanzapine [143], olanzapine with valproate, and lithium [144]. Corticosteroid-induced depression may respond to lithium alone [145]. However, lithium can cause leukocytosis and thrombocytopenia [146] while mood stabilizers and antiepileptics (eg, carbamazepine and valproic acid) can cause thrombocytopenia and neutropenia [147]. Since symptom onset can be rapid, educating patients and their families about these common psychiatric effects of steroids can facilitate timely assessment and management [148].

EXISTENTIAL DISTRESS AND SPIRITUAL WELL-BEING

Overview:

Patients with GVHD may experience existential distress, defined as loss of meaning or purpose and spiritual despair [149–151]. Existential distress is a psychological response that limits one’s ability to find peace and maintain hope, and often occurs along with loneliness and low self-esteem [152]. GVHD can cause pain, physical and emotional changes, isolation, and changes in relationships. Its prolonged course [153] increases the risk for morbidity and mortality [108]. GVHD can challenge one’s existential well-being, as this condition is often unpredictable with significant prognostic uncertainty [108]. For example, when facing the frequent and often unexpected exacerbations and physical sequalae of GVHD, patients may ask, “Why is this happening to me?” Broader questions about meaning and purpose may rise to the forefront as patients endure severe pain and suffering while grappling with the knowledge that the condition might result in long-term disability or even death [154].

Management:

Dignity therapy and meaning-centered psychotherapy are two evidence-based approaches to manage existential distress and suffering in patients with cancer. Both psychotherapeutic modalities foster discussions on meaning, purpose, and personhood, which are often threatened by significant symptom burden and related feelings of despair [149,155]. They may incorporate the use of spirituality depending on the role it plays for a patient. Spirituality is defined as a framework through which one considers the meaning and value of their life, which may involve traditional religious systems [156]. Spirituality is a known protective factor for patients with chronic illness or medical challenges [157]. For example, patients with high levels of spiritual absence [158] may be more likely to die 1-year post-HSCT [159]. Unfortunately, the spiritual needs of many patients with serious illnesses, including those with GVHD, may be overlooked in disease management and healthcare settings, despite patients’ desire for these needs to be addressed [160]. While robust spiritual well-being scores have been found among autologous SCT patients, these scores have been observed to decline in patients 90 days post-allogeneic SCT [161]. Further, chronic GVHD has been associated with worse spiritual well-being [162]. Longer duration of chronic GVHD is associated with lower levels of spiritual well-being as well as other aspects of well-being (eg, overall QOL, physical well-being) [156].

PSYCHOSOCIAL INTERVENTIONS TAILORED TO THE NEEDS OF PATIENTS WITH GVHD

Although a robust body of evidence documents the high symptom burden and poor QOL experienced by patients living with chronic GVHD, few supportive care interventions have been developed and tested to address the specific psychosocial care needs of this population [25]. The Horizons Program is one of the only existing supportive care interventions that has been empirically investigated in this patient population [163]. The Horizons Program entails a multidisciplinary group coping skills intervention for patients living with moderate or severe chronic GVHD. It is coled by a behavioral health clinician and transplant care expert. Small groups, consisting of 4 to 6 patients, meet virtually for 8 sessions to enhance patients’ understanding of chronic GVHD signs, symptoms, and treatment. These sessions also aim to teach coping skills designed to strengthen patients’ capacity to manage the short- and long-term consequences of this disease. Findings from a pilot randomized controlled trial of the Horizons Program have demonstrated feasibility and preliminary efficacy of the intervention for improving QOL and reducing depression symptoms compared to usual care [163].

A summary of commonly used psychosocial interventions for patients living with cancer is included below in Table 2. Of note, these techniques have largely not been tested among those living with chronic GVHD.

Table 2.

Psychosocial Interventions and Proposed Applications to Chronic GVHD

Intervention	Application
Cognitive-behavioral therapy	Identify and challenge maladaptive thoughts and beliefs as well as work toward behavioral change; develop coping strategies to manage the physical, functional, and socio-emotional impact of GVHD symptoms
Acceptance and commitment therapy	Develop psychological flexibility, acceptance, and commitment to values to promote overall well-being and improve quality of life
Mind-body interventions	Develop awareness and reduce judgment of thoughts, feelings, and bodily sensations to improve stress and symptom management
Existential interventions	Focus on meaning and purpose to address hopelessness and demoralization
Supportive psychotherapy	Create a psychologically safe and validating environment to explore thoughts and feelings
Physical activity and exercise	Promote healthy movement and physical fitness to improve energy, mood, and strength

PALLIATIVE CARE FOR HSCT SURVIVORS WITH GVHD

Palliative care has been shown to improve experiences for both patients and their family caregivers in cases of severe chronic GVHD [164–166]. Palliative care can address numerous clinical domains, including symptom management, goals of care, advance care planning, emotional support, and spiritual support [164–170].

Despite strong rationale for the integration of specialized palliative care team members into the interdisciplinary transplant team, there may be attitudinal and logistical barriers to the routine integration of appropriate components of palliative care in the care of HSCT recipients. These barriers include the often unpredictable clinical course of HSCT, absence of a clear transition between curative and palliative phases of treatment, and limited experience of members of transplant teams in the co-management of patients with palliative care teams [171–174]. A recent national study examining HSCT recipients’ perceptions about palliative care demonstrated that more than 40% of these recipients reported limited knowledge and familiarity with palliative care, and those who were more knowledgeable about palliative care were more likely to report a positive perception of it [167]. Collaboration between transplant and palliative care clinicians can ensure that transplant recipients are fully informed about palliative care options.

CARE COORDINATION FOR HSCT SURVIVORS LIVING WITH GVHD

Patients hospitalized to undergo HSCT and those in the acute recovery period afterward usually have the most interaction with their care team either in the hospital or during weekly follow-up visits in the first 100 days post-transplant [175]. However, as a patient progresses past the first 100 days after transplantation, the frequency of interaction with the transplant care team decreases [176], and it can be difficult for survivors to find local medical providers who can recognize GVHD signs and symptoms, initiate appropriate treatment, and monitor treatment efficacy and toxicity.

HSCT survivors are at risk of developing long-term complications secondary to the transplant process [177,178] which include impairments to QOL, psychosocial concerns, financial challenges, and sexual health or fertility issues [179]. Some of these complications may lead to nonrelapse mortality, while others directly impact QOL.

Patients with GVHD can have significant unmet care coordination needs. Many survivors report that they are not provided with the information or training that they need for self-care or symptom management (ergo, this entire series). The persistence of symptoms without sufficient tools for self-management may lead to frustration and resentment [8,176]. Patients and clinicians have reported the need for more information and care coordination around GVHD to be provided in the form of survivorship care plans, which generally include (1) treatments received, (2) recommended follow-up, (3) health maintenance, including vaccinations, (4) survivor and clinician resources, and (5) monitoring for late complications [180].

The complexity of chronic GVHD warrants a multidisciplinary team approach by medical oncology, palliative care, psychiatry, psychology, nursing, social work, physical/occupational therapy, dermatology, gynecology, ophthalmology, as well as others [8]. HSCT survivorship clinics are important care model for patients with chronic GVHD and their caregivers to access treatment and support [181]. Because survivorship clinic providers are already closely monitoring for and managing late-onset symptoms, they are uniquely positioned to assist with symptom management for GVHD. Survivorship clinics should screen for psychosocial distress and well-being, and monitor QOL using validated assessment measures that are scheduled at standardized time points and administered longitudinally while providing patient education and working to empower patients to actively engage in their health to optimize long-term outcomes [182]. Peer-to-peer support could help patients with GVHD manage expectations and navigate the uncertainty of GVHD [183].

Effective care coordination for patients with GVHD and their families should entail (1) identification of a key contact person, (2) early assessment, recognition, and diagnosis of symptoms, (2) immediate treatment of GVHD symptoms and referrals, (3) ongoing monitoring of symptoms to avoid under- or over-treatment, and (4) supportive care to prevent morbidity and additional complications [8,184]. Routine physical exams should be performed to assess functional status, nutritional status, and involvement of organ systems. When warranted, patients may undergo additional testing (eg, neuropsychological testing). Adequate psychosocial support for patients with chronic GVHD can validate patients’ concerns and create opportunities for significant improvement in emotional and psychological health and subsequent clinical outcomes. An important part of an effective care coordination model is a patient navigator to anticipate and assist with the complexities and barriers within healthcare systems and provide culturally informed education and psychosocial support to enhance patients’ QOL [184]. Other components of this model include the use of telemedicine, survivorship clinics, self-management and educational interventions, standardization of evidence-based protocols to inform clinical pathways, and psychosocial and financial support. Use of telemedicine as part of dedicated long-term follow-up programs may contribute to better outcomes in patients with chronic GVHD to minimize time away from life roles and responsibilities [185].

CONSIDERATIONS FOR SPECIAL GROUPS

Pediatric and Adolescent and Young Adult (AYA) Patients

While chronic GVHD has a lower incidence in pediatric and AYA patients, it can shorten life expectancy and adversely affect QOL [186]. Factors such as social isolation, immunosuppression, and disruption of daily routines can affect younger patients significantly. Pediatric and AYA patients may be affected by inability to return to physical activities (eg, sports), self-consciousness about physical changes from treatment, and withdrawal from relationships with peers. Pediatric survivors of HSCT are at high risk for anxiety, depression, and PTSD [187,188]. Among AYA patients with hematologic malignancy, 46% show symptoms of post-traumatic stress, 28% met criteria for depression, and 23% met criteria for anxiety [189,190]. AYA patients may encounter issues with medication dependency, fear of the future, educational attainment, employment, sexual dysfunction, changes in roles and relationships, and social adjustment [191]. Survivors of pediatric HSCT who experienced GVHD had slower processing speed and weaker verbal learning [192]. Screening and intervention strategies for neurocognitive dysfunction in survivors are available, but screening is often underutilized. Depending on individual deficits, interventions for those with neurocognitive dysfunction include school interventions, cognitive-behavioral therapy, skill training, and computerized cognitive training [193,194].

Collaborative care models for pediatric populations should incorporate a care manager who can provide guidance to patients and their families on various aspects of care coordination, such as managing medications and infection risk, supporting healthy behaviors and dietary choices, and communicating with HSCT clinicians [153,176]. For pediatric survivors of HSCT living with chronic GVHD, frequent assessments of bothersome symptoms that are based on the words children use to describe their symptoms are crucial [195]. Child life specialists, social workers, and/or psychologists should be integrated in chronic GVHD management to teach coping skills for managing dynamic symptom profiles, undergoing repeated procedures, and living with a chronic illness [196,197]. Culturally appropriate educational materials, peer-to-peer networking, and camp programs can help reduce isolation. When available, palliative care should be engaged to address pain, fatigue, and other distressing symptoms. Another major challenge occurs when transitioning youth with chronic GVHD to adult care [198]. One in four pediatric patients will be lost to follow-up within 10 years post-allogeneic HSCT [199]. To ease the transition process, patient and family education personalized to each survivor should be integrated into transition practices [198].

Geriatric Patients

Older patients undergoing HSCT have unique care considerations and psychosocial needs [200]. The risk of developing chronic GVHD increases with age [201]. Older adults face a greater risk of additional complications, including delirium at time of transplantation, post-transplantation infectious processes like Clostridium difficile infection, and a higher risk of developing secondary malignancies like myelodysplastic syndrome and acute myeloid leukemia [59,202,203]. Notably, older patients undergoing HSCT are at an increased risk of overall mortality following transplantation [204]. Poor outcomes are associated with regimen-related toxicities, higher risk of relapse, and barriers to healthcare access [205]. Researchers have proposed the comprehensive geriatric assessment (CGA) as a risk stratification tool for treatment toxicity and survival in the treatment of hematologic malignancies and allogeneic HSCT [206,207]. Performing the CGA is a multidisciplinary process that assesses the medical, psychosocial, and functional limitations of older adults. Specific domains of CGA, such as instrumental activities of daily living, cognition, and gait speed, reflect functional reserve and vulnerabilities and may predict survival beyond chronologic age and performance status [208].

While there is no evidence suggesting that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD [209], the increased risk of complications and mortality in this population can compromise psychological well-being and QOL. Additional research on the psychosocial impacts of GVHD and its treatment in older adults will inform gaps in current care offerings and directions for future interventions.

CONCLUSION AND FUTURE DIRECTIONS

Very limited research has focused on the psychosocial needs of people living with GVHD. A biobehavioral framework that considers the interaction between behavioral, psychological, socioenvironmental, and biological processes allows for a more comprehensive approach to care for patients with GVHD. There is a critical need for observational research identifying types of psychosocial needs and how they change over an unpredictable disease course as well as development, adaptation, and testing of targeted interventions to fill the substantial gap in supportive care intervention research across the lifespan for this survivorship population. Pharmacological treatments for anxiety, depression, sleep disturbances, and fatigue in patients with GVHD are available, but the benefits of these medications must be weighed against potential hematologic adverse reactions. Psychiatric sequelae must be carefully monitored in patients taking corticosteroids for the treatment of GVHD. Palliative and psychiatric care can improve experiences of patients with chronic GVHD and their families. Transplant teams should be prepared to collaborate with palliative care and subspecialty providers from other medical and supportive disciplines in a timely manner to ensure that patients’ QOL goals are being adequately addressed. Care coordination models that include case managers and/or patient navigators can help bridge much-needed gaps in post-HSCT care, particularly for pediatric and AYA patients with GVHD. Since life with GVHD can be isolating, supportive interventions that connect patients with peer support could foster resilience, social support, QOL, and well-being.

Across the lifespan, patients face unique challenges related to the underlying inflammatory processes contributing to GVHD, frequent and unpredictable exacerbations of symptoms requiring interactions with medical providers, and limited availability of programs to provide tools for self-management. Pediatric and AYA patients with GVHD should be assessed for coping, social withdrawal, and neurocognitive dysfunction. Multidisciplinary teams, including child life specialists, social workers, and psychologists, can provide psychosocial support and coping skills education to pediatric and AYA patients. Periods of transition from pediatric to adult care, as well as inpatient to outpatient care, represent an opportunity for care teams to proactively ensure that survivors with GVHD can manage their symptoms and recognize when to request additional help from their providers. The psychosocial needs of older adults with GVHD, another population at risk for severe post-transplant complications, warrant further characterization. The power of the biobehavioral framework lies in the consideration of factors ranging from molecular drug mechanisms to healthcare systems-level initiatives to address the interaction between patients’ physical and mental health. It is imperative that we strive to advance research informed by a biobehavioral framework and translate research findings into clinical practice to improve the lives of those living with GVHD.