Introduction

The current population of > 100,000 hematopoietic cell transplantation (HCT) survivors in the USA is projected to increase fivefold by 2030, with 14% of the population with age < 18 years and 25% with age ≥ 60 years at transplantation [1]. The physical, psychological, and social sequalae of HCT have an adverse impact on mortality and morbidity of these survivors even many years after HCT [2,3,4,5,6,7,8, 9••, 10].

The goal of this article is to summarize the current information about medical and psychosocial complications and review the current status of screening and management of these complications to facilitate better care of HCT survivors. I also briefly overview the unique physiological and psychosocial challenges of survivorship in the pediatric and adolescent young adult population. I do not discuss chronic graft vs host disease which is a major complication after allogeneic HCT and a risk factor for a host of other sequelae, in detail in this review. I also highlight the barriers and models of care delivery to address these complications and identify areas of focus for future research priorities and clinical practice.

Medical Complications After HCT

There is an extensive literature on the occurrence of late medical complications/chronic health conditions including diseases of the cardiovascular, pulmonary, and endocrine systems, renal and hepatic dysfunction, infertility, iron overload, bone and metabolic problems, infections, and secondary cancers after HCT. Additionally, there are abundant reports on physical sequalae affecting the survivors such as chronic pain, fatigue, sexual dysfunction, and cognitive impairment. Table 1 outlines these complications, frequency of occurrence, and risk-adapted screening measures.

Table 1 Late complications after hematopoietic cell transplantation
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Figure 1 highlights the traditionally known risk factors associated with these late effects. The spectrum of late effects may continue to evolve along with changes in the conditioning regimens such as higher use of reduced intensity regimens, decreased use of TBI-based regimens, donor sources, and GVHD prophylaxis regimens such as use of post-transplant cyclophosphamide [11, 4]. Studies are starting to examine the mechanistic aspects of these late effects including the role of microbiome, accelerated aging with telomere shortening, shift in body fat distribution, endothelial dysfunction, and chronic inflammation/immune dysregulation in producing these late effects [12,13,14,15,16]. Improved knowledge about underlying mechanism can inform the development of personalized risk-reduction strategies and set the stage for much-needed tailored interventions to prevent and treat these complications.

Fig. 1
figure 1

Risk factors that influence occurrence and prevalence of late effects after survivorship

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Psychosocial Complications After HCT

Psychological sequelae following allogeneic HCT have been described in detail such as depression, anxiety, perceived stress, adverse coping, social isolation, poor mental functioning, financial burden, and inability to return to work. Table 2 describes the prevalence and risk factors for these complications. The recent COVID-19 pandemic has exacerbated the susceptibility to adverse biobehavioral sequelae [17]. HCT survivors and their caregivers have identified these concerns as critical focus areas to be focused on during care delivery for post-HCT period [18].

Table 2 Prevalence and risk factors for psychosocial problems after HCT
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A multitude of studies has reported the impact of these medical and psychosocial complications on the quality of life for HCT survivors. Guidelines for post-HCT care recommend periodic screening and counseling for psychosocial difficulties and deficits especially depression after transplant, at 6 and 12 months, and annually thereafter [19]. They also recommend regular assessments of spousal/caregiver psychological adjustment and family functioning as a caregiver is now identified as an integral part of a patient’s transplant journey. Universal screening for financial distress should be added to the usual patient-reported outcomes assessments since it is prevalent and affects patient outcomes [20].

Specific Considerations for Pediatric/Adolescent and Young Adult (AYA) Populations

Pediatric and AYA patients and survivors of pediatric HCT have a high burden of chronic health conditions such as endocrine abnormalities including growth hormone deficiency, impaired fertility, neurocognitive deficits, cardiopulmonary and renal problems, infectious complications, and secondary cancers [21]. Though good outcomes have been reported after allogeneic HCT in pediatric and adolescent patients with non-malignant disorders, the risk for secondary neoplasms is high especially in patients with Fanconi’s Anemia and marrow failure syndromes [22].

Adverse psychosocial outcomes including greater symptom burden, cognitive and academic deficits, depression, anxiety, and post-traumatic stress are also quite common in this vulnerable group of survivors as compared to healthy peers. HCT and its sequelae may limit the AYA survivors to achieve milestones such as graduating college, selecting a career, establishing employment, and achieving socioeconomic independence from parents [23, 24].

The unique challenges of pediatric and AYA survivors of HCT indicate the need to develop screening programs and interventions specifically tailored to them [25,26,27].

Prevention and Treatment of Late Effects After HCT

Many large studies show that the life expectancy for HCT survivors continues to lower than that of their age- and gender-matched peers from the general population indicating the high burden of late effects [5, 28]. This underscores the need for evidence-based preventive and therapeutic interventions specific for HCT survivors with the goal of mitigating the risks and improving outcomes following HCT. Comprehensive guidelines for screening and prevention have been published and are in the process of being updated soon [19]. A recent trial examining the role of individualized survivorship care plans generated using registry data showed reduced distress and improved mental domain of quality of life among 1–5-year HCT survivors [29].

Table 3 describes current preventive practices and treatments for these complications. Continued surveillance for specific complications for early diagnosis and treatment, adequate psychosocial support, and encouraging healthy lifestyle behaviors may help in reducing the long-term morbidity associated with these complications. Vaccinations are an important component of the preventive care for these patients. Vaccines for SARS-CoV-2 likely have positive risk benefit but more studies are needed to understand short and long-term protection with it.

Table 3 Prevention and treatment for late complications
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Survivorship Care Delivery Models

Given the increased risk of developing a wide range of adverse late effects, there is an urgent need to develop and implement effective models for delivering survivorship care. The overall goal of survivorship care is early diagnosis of treatment-related complications, potentially allowing for early intervention leading to reduction in morbidity and mortality. These models should be based on the three-step approach to prevention for these complications. The first step or primary prevention would include health promotion activities including using transplant as a “teachable moment” for promoting healthy behaviors, increasing awareness, and preemptively trying to address risk factors including altering therapeutic exposures for these complications. Secondary prevention would include screening for early detection of late effects and instituting appropriate treatments. Screening should be individualized based on sociodemographic and clinical factors. Tertiary prevention would be targeted at decreasing the morbidity and mortality from these complications such as rehabilitation strategies and disability limitation.

Implementing the above approach requires integration of all the relevant stakeholders such as transplant team, primary care or oncology physician, psychologist or psychiatrist, other medical specialists, social workers, and financial counselors. Figure 2 outlines the barriers in the ability to deliver accessible, equitable, and affordable survivorship care. Establishment of multidisciplinary long-term follow-up clinic can help deliver guideline-driven screening and management of late effects; however, the challenges and lack of standardization for such clinics was highlighted by a survey done by the American Society for Blood and Marrow Transplantation (ASBMT) Practice Guidelines Committee [30]. A more recent survey carried out by the British Society of Blood and Marrow Transplantation and Cellular Therapy data registry reflected on growth of survivorship efforts possibly driven by increasing recognition of late effects and survivorship by clinicians, health service policy, and JACIE accreditation standards mandating survivorship care though challenges specially with resource constraints and availability of specialists persist [31••].

Fig. 2
figure 2

Barriers to transplant survivorship care delivery

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With the increased focus on virtual medicine because of the pandemic, there is an opportunity to leverage virtual technologies to deliver well-rounded risk stratified survivorship care to HCT survivors incorporating psychosocial screening and interventions [32]. This can help encourage health-related self-efficacy in patients, increase health system capacity, and promote adaptive HCT survivorship. Online programs may help address some of the barriers in providing medical care such as distance, varying needs and lack of standard follow-up care. Recently, the INSPIRE (an INternet-based Survivorship Program with Information and Resources) study found no differences between the study arms on the primary endpoint of aggregated outcomes of cancer and treatment distress, depressive symptoms, physical dysfunction, and fatigue though there was significant improvement in distress alone for those in the INSPIRE + problem-solving treatment arm [33].

Areas of Focus for Future Research Priorities and Clinical Practice

Future studies in large, representative samples with more focus on special populations—children, adolescent and young adults, older adults, racial/ethnic minority patients are needed to describe the changing landscape of late effects with the ongoing changes in transplant practice. MOSA study is a great example of a well-designed matched cohort study of late effects after HCT and includes a matched cohort representing the general population allowing direct comparisons [34•]. There is an urgent need to identify biomarkers for detection and prognostication of the late effects. Leveraging Artificial Intelligence and Machine Learning techniques develop predictive models for risk using transplant- or patient-related factors including social determinants of health can help with earlier diagnoses of some of these late effects, improve clinical decision-making, and ultimately lead to better health outcomes for HCT survivors. More research is also required to develop and test effective ways of reducing long-term toxicity of HCT, early prevention and rehabilitation strategies, and social and financial support (emotional, informational, and logistical) interventions. HCT caregivers are a vulnerable group with persistent unmet psychosocial, medical, financial, and daily activity needs throughout the transplant continuum. Research is needed to address their needs and better support them to improve outcomes for HCT survivors, caregivers, and survivor-caregiver dyads.

In routine clinical practice, there is a compelling need to create robust community-based resources that coordinate with transplant centers to help deliver care at point of need to HCT survivors. Workforce recruitment/retention/training and infrastructure development is essential to provide optimal care and address the needs of a growing pool of HCT survivors. Educational initiatives to improve awareness about the late effects targeting different stakeholders can help improve engagement and improve resilience and coping. Partnerships with payers will be required to test and implement new models of care delivery for HCT survivors including application of technology or use of patient navigators.

Conclusions

With advances in treatment practices and survival after HCT, there is an increasing recognition of the medical and psychosocial complications which continue to increase in incidence after HCT. Multiple initiatives in the field of HCT are beginning to identify the gaps in practice and research and recognize the importance of integrating patient-centered outcome screening and interventions with the goal to improve long-term health outcomes after HCT [18, 35]. The role of educational initiatives to empower and engage patients and their caregivers in improving their psychosocial health is extremely valuable. An individualized, risk-adapted, and multidisciplinary approach is required for follow-up care for HCT survivors.