Survival, quality of life, and late complications after hematopoietic cell transplantation in adults

INTRODUCTION — Hematopoietic cell transplantation (HCT) has the potential to cure leukemias, lymphomas, hemoglobinopathies, and other disorders, but transplantation is associated with high rates of complications and mortality. Complications and mortality are highest in the first year after HCT, due to drug toxicities and the intensity of immunosuppression, but generally decline with time. Late complications (ie, >1 year after transplantation) can affect many organ systems, impair the quality of life (QoL), and increase mortality, but most patients can eventually return to work and experience near-normal QoL.

This topic will discuss survival, quality of life, and late complications after allogeneic and autologous HCT in adults.

Complications encountered in the first year after transplantation ("early complications"), clinical manifestations of acute and chronic graft-versus-host-disease, and second cancers after HCT are discussed separately.

●(See "Early complications of hematopoietic cell transplantation".)

●(See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

●(See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

●(See "Secondary cancers after hematopoietic cell transplantation".)

Transplantation outcomes for specific diseases and in children are discussed separately in those topics.

OVERVIEW OF LATE COMPLICATIONS — HCT is associated with high rates of complications and mortality. Complications and mortality are highest in the first year due to drug toxicities and the intensity of immunosuppression, but they generally decline over time. Most patients are eventually able to return to work and experience near-normal quality of life (QoL). Importantly, a healthy lifestyle and appropriate preventive care can attenuate the risk for adverse outcomes.

CONTRIBUTING FACTORS — Outcomes and late complications with HCT are affected by the underlying illness, comorbid conditions, aspects of transplantation, and complications that arise in the first year after HCT:

●Underlying illness – The underlying illness (eg, acute leukemia, hemoglobinopathy), prior treatment (eg, chemotherapy, radiation therapy), complications (eg, chemotherapy-associated cardiotoxicity, iron overload from multiple transfusions, recurrent infections), and disease status at the time of transplantation (eg, complete remission versus residual disease) affect survival, QoL, and the nature and severity of late complications.

●Aspects of transplantation – Development and severity of late complications are influenced by the type of HCT conditioning regimen (eg, chemotherapy, radiation therapy), intensity of the regimen (eg, myeloablative, reduced intensity, nonmyeloablative), type of graft (eg, autologous versus allogeneic), and immunosuppressive regimen for graft-versus-host-disease (GVHD). (See 'Survival after allogeneic HCT' below and 'Survival after autologous HCT' below.)

●Comorbid conditions – Comorbid cardiovascular disease, diabetes mellitus, and pulmonary, hepatic, and renal conditions may exacerbate or reduce tolerance for late complications.

●Early complications after HCT – Early complications, including infections, cytopenias, and manifestations of acute and chronic GVHD are discussed separately. (See "Early complications of hematopoietic cell transplantation" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

SURVIVAL — The greatest risk of death in the first years after transplantation is recurrence of the underlying disease; other common causes of death include infection, second cancers, and organ system dysfunction. Survival is influenced by whether the patient underwent allogeneic or autologous HCT.

Survival after allogeneic HCT — Life expectancy after allogeneic HCT is lower than that of the general population. Causes of death vary with the time since transplantation, age, and the underlying illness and its prior treatment. (See "Secondary cancers after hematopoietic cell transplantation" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Overall survival (OS) after allogeneic HCT is lower than that of the general population for at least 10 to 30 years after transplantation [1-9]. Relapse of the underlying disease is the most common cause of death in the first four years after transplantation, but patients who are relapse-free beyond this point have a high probability of long-term survival [10]. The predominant causes of nonrelapse mortality (NRM) after allogeneic HCT are chronic graft-versus-host-disease (cGVHD), infection, second cancers, and organ system dysfunction.

Informative studies of survival after allogeneic HCT include:

●In a study of more than 10,000 patients, 10-year OS was estimated to be 85 percent in those who remained relapse-free two years after myeloablative allogeneic HCT for acute leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia [1]. At two years, the mortality rate was higher than that of the general population, but the relative risk for death declined over time. Except for patients with lymphoma, the increased rate of death did not return to that of the general population during the median follow-up of nine years.

●In a single-institution study of 1479 individuals who survived ≥2 years after allogeneic HCT, 15-year OS was estimated to be 80 percent [5]. Compared to age-, sex-, and calendar year-matched general United States population, the standardized mortality ratio (SMR) was 9.9 (95% CI 8.7-11.2) and was highest in years 2 to 5 post-HCT (78-fold increase); mortality rates remained elevated for at least 15 years. Disease relapse (29 percent) was the most common cause of premature death; two-thirds of relapses occurred in years 2 to 5. The most common causes of NRM were cGVHD (22 percent), infection (11 percent), second cancers (7 percent), pulmonary complications (5 percent), cardiac toxicity (2 percent), and other treatment-related events (8 percent). Compared with patients without cGVHD, NRM was increased 2.7-fold for those with cGVHD.

Survival after autologous HCT — The mortality rate after autologous HCT remains elevated for decades, but it approaches that of the general population over time. Disease relapse is the most common cause of death in the earlier years after autologous HCT, but infections, organ dysfunction, and second cancers account for most later deaths. Unlike allogeneic HCT, patients who undergo autologous HCT do not experience graft-versus-host disease (GVHD).

Examples of outcomes after autologous HCT include:

●The estimated 20-year OS was 80 percent (95% CI 78-83 percent) in a single-institution study of 1672 patients who were relapse-free for ≥5 years [2]. Regardless of the patient's age, life expectancy was one-third lower than the general population, and mortality rates remained elevated four- to ninefold for at least three decades after transplantation. Leading causes of death were disease relapse, second cancers, infection, respiratory disease, and cardiovascular disease [2].

●A single-institution study of 309 patients who underwent autologous HCT for lymphoma reported that the overall mortality rate approached that of the general population over time, but it did not return to normal even after 15 years of follow-up [11]. NRM surpassed relapse as the main cause of death approximately eight years after transplantation. The most common causes of NRM were respiratory failure (31 percent), cardiac toxicity (15 percent), second cancers (15 percent), and infection (13 percent). In the first two years after HCT, respiratory failure and infection were the most common causes of NRM, but second cancers predominated in later years.

QUALITY OF LIFE

Key determinants of QoL — Quality of life (QoL) is a multidimensional concept that includes the individual's perception of physical function, psychological state, independence, financial well-being, and social and sexual satisfaction. QoL is influenced by the individual's goals, expectations, cultural standards, and value systems. There is no consensus regarding the precise definition of QoL, its component parts, or the optimal assessment instruments. Health-related QoL and its assessment are discussed in detail separately. (See "Evaluation of health-related quality of life (HRQL) in patients with a serious life-threatening illness".)

Key determinants of QoL after HCT are discussed in the sections below.

Physical function — Physical function refers to the ability to conduct a variety of activities, ranging from self-care to more vigorous activities that require substantial ability, strength, or endurance [12]. Functional limitations and symptoms (especially fatigue) affect a significant proportion of long-term survivors, but most transplant survivors resume routine activities over time. The type of transplantation can affect physical function outcomes.

●Allogeneic HCT – Prior to allogeneic HCT, physical function is typically inferior to that of the general population (due to the underlying disease and its treatment) and a nadir for physical function is generally observed 30 to 100 days after transplantation [13,14]. A prospective study that included 61 patients reported that physical function one to five years after allogeneic HCT was comparable to that of the general population [13]. Other studies also documented functional improvement within one to four years after transplantation [15-18]. Factors associated with impaired recovery of physical function at one year include severe chronic graft-versus-host disease (cGVHD), pretransplant physical impairment, and family conflict [14,19].

Major functional limitations (eg, reduced mobility, impaired performance of usual activities), frequent doctor visits, or hospitalization in the previous year were reported by 18 to 34 percent of patients 1.5 to 5 years after transplantation [20-22]. The most common physical complaints at two years were sexual difficulties (36 percent), fatigue (33 percent), painful joints (20 percent), skin changes (16 percent), other pain (11 percent), and mouth sores (9 percent) [23]. Compared to individuals without cancer, allogeneic HCT survivors reported small to moderate physical impairments at 5 to 10 years post-transplant [24-26].

A multicenter study randomly assigned 105 patients undergoing allogeneic HCT to routine social contacts versus a partially supervised exercise program before, during, and up to eight weeks after hospital discharge [27]. Compared with control patients, those assigned to the exercise program had better ratings on measures of fatigue, physical fitness, and global distress.

●Autologous HCT – Patients generally experience a nadir of physical function between 10 days and 6 weeks after autologous HCT due to early toxicity (eg, nausea, vomiting, mucositis) associated with the conditioning regimen [28-31]. This impairment progressively improves and most patients match or exceed their baseline by three months, six months, and/or one year after transplantation [12,28,30,32-34]. A prospective study that included 69 patients who underwent autologous HCT reported that physical function was comparable to that of the general population after one to five years [13].

Fatigue is common before, during, and after autologous HCT, but rates vary with the underlying disease [35-37]. In one study, one year after autologous HCT, most patients reported good appetite, stable weight, and little difficulty sleeping [32]. However, three years after autologous HCT, approximately two-thirds of patients reported persistent difficulty with activities such as taking a long walk or carrying a shopping bag [33]. A prospective single-institution study reported that QoL was comparable in patients undergoing inpatient versus outpatient autologous HCT [38].

Employment/financial — The ability to return to employment, homemaking, or studies is referred to as role functioning. In general, rates of employment improve over time, but patients may experience denial of health or life insurance. Financial worries in transplant survivors are often underestimated by caregivers.

●Allogeneic HCT – Role functioning prior to allogeneic transplantation is lower than population norms due in part to the underlying illness and/or comorbid conditions; this is exacerbated by the prolonged hospitalization associated with allogeneic HCT. In general, most patients who survive relapse-free can expect to resume work, school, and other roles in the community.

Role functioning is impaired in the first 100 days after transplant, but by one year it is typically comparable or slightly improved compared with baseline and continues to improve over time [13,39-41]. Between one and four years after transplantation, two-thirds to three-quarters of patients have returned to work or school [5,18,21,23]. For at least three years, survivors continue to have comparable or slightly impaired role function compared with individuals without cancer [24,26,41,42]. However, by 10 years, allogeneic HCT survivors did not differ from controls (ie, age-, race-, and sex-matched individuals without cancer) with regard to full-time employment [43]. Among all patients who were transplanted (including those who died or relapsed), 20 to 34 percent had returned to work between years 1 and 5 [21].

Compared with their siblings, long-term allogeneic transplant survivors are less likely to be married and more likely to have health-related issues preventing them from holding a job and difficulty maintaining health insurance or acquiring life insurance [5,44-47]. Reduced role functioning and a delayed return to work was more common in women and in patients with extensive cGVHD [19,48,49].

●Autologous HCT – There are typically substantial deficits in role functioning in the pre- and peri-autologous HCT periods, but this improves rapidly [32,33]. At three years, transplant survivors still had deficits compared to a reference population and at five years half of patients reported limitations in work or household activities [33,50]. However, by 10 years, rates of employment were not different than age-, sex-, and race-matched non-HCT controls [43]. A systematic analysis reported that pretransplant psychological distress predicted a lower likelihood and/or delayed return to work [51].

Anxiety/depression — Psychological distress (eg, anxiety, depression) is common before, during, and after HCT, but generally improves over time and approaches rates in the general population. Contributing factors include physical and cognitive effects of the underlying disease and its treatments, fear of relapse and death, a sense of isolation or stigmatization, and financial insecurity [12].

Moderate to severe depressive symptoms were reported by 25 to 40 percent of patients in the first year after transplantation, but it is unclear if this differs from healthy control populations [20,29,52,53]. Several studies have reported that three or more years after transplantation, psychological distress is comparable to that of the normative population [13,21,24,43]. A single-institution study of 84 patients reported that depressive symptoms declined, QoL improved, and patients drank less alcohol over time [54]. However, other studies have reported that emotional functioning was impaired relative to healthy controls 5 to 10 years after HCT [25,26,43,55]. A European study reported that transplant survivors had higher rates of suicide and accidental death than the general population [56].

A systematic analysis reported that depression after transplantation was associated with psychological distress prior to HCT and female sex [51]. Psychological distress may be exacerbated by cGVHD, but it can occur after allogeneic HCT even without cGVHD [25,44,57]. Other studies reported that distress was associated with lower socioeconomic status, lower income, lack of employment, and unmarried status [58,59]. Older patients were not more compromised than younger ones [29].

A variety of psychological interventions have been examined in patients undergoing transplantation. Although small to medium effects have been reported, there is no consensus regarding the most effective strategies for relieving psychological distress after HCT [60-62].

Social/sexual well-being — Social well-being refers to participation in routine social activities, receipt of support, feelings of closeness, and perceived communication with a partner and other loved ones.

One study reported that marital satisfaction six months after HCT did not differ from pretransplantation satisfaction [53]. One study found that social impairment lessened over the first year after either allogeneic or autologous HCT and became comparable to population norms [13]. In another study, compared to allogeneic recipients, a higher percentage of patients who underwent autologous HCT enjoyed socializing with relatives and friends during the first year, but this difference did not persist after 12 and 24 months [23]. Among allogeneic survivors, general social participation was below population norms from baseline until 12 months after transplantation [16]. Social well-being did not differ from population norms after 10 years beyond allogeneic HCT [24,43].

HCT can affect sexual function, satisfaction, and intimacy [53,63,64]. Patients' concerns include decreased libido, fatigue, infertility, erectile/ejaculatory dysfunction, premature menopause, dyspareunia, and vaginal dryness, narrowing, or fibrosis. Changes in body image, anxiety, depression, and worries about disease recurrence may also contribute to sexual dysfunction/satisfaction. Despite the prevalence of sexual dysfunction, about half of patients report that their health care provider did not discuss potential effects on sexuality prior to HCT and had not discussed them in follow-up visits at one and three years after transplantation [65].

Further discussion of sexual dysfunction in female cancer survivors is presented separately. (See "Overview of sexual dysfunction in female cancer survivors".)

EARLY COMPLICATIONS — Early complications refer to conditions that are manifest in the first year after transplantation and are described separately. (See "Early complications of hematopoietic cell transplantation".)

LATE COMPLICATIONS

Overview of late complications — Late complications are those that are manifest beyond one year after transplantation. Some late complications (eg, chronic graft-versus-host disease [cGVHD]) may have begun earlier, while others (eg, second cancers) are first noted years after transplantation. Some late complications (eg, cardiovascular events, bronchiolitis obliterans, end-stage renal failure) contribute to nonrelapse mortality (NRM), while others (eg, dry eyes, xerostomia, avascular necrosis) may be a source of substantial morbidity and impaired quality of life (QoL), but do not reduce overall survival (OS) [10,66,67].

Most transplant survivors experience at least one late complication of HCT. In a large single-institution study, the cumulative incidence after five years of any nonmalignant late effect was 45 percent after autologous HCT and 79 percent after allogeneic HCT; 3 and 26 percent, respectively, experienced ≥3 late effects [68]. In a study with median follow-up of seven years, nearly 1800 adult survivors of allogeneic HCT had higher rates of hospitalization and all-cause mortality than other cancer survivors or the general population [9]. In that study, transplant survivors had more hospitalizations or deaths with infections, more respiratory complications, and increased risk for digestive, skin, and musculoskeletal complications compared with non-HCT cancer survivors; rates of circulatory complications and second cancers were similar.

Infectious diseases — Infections are a common cause of morbidity and NRM following HCT. An overview of infections after HCT is provided separately. (See "Overview of infections following hematopoietic cell transplantation".)

Immune reconstitution typically requires 12 to 18 months and, consequently, the risk of infection is highest in the first two years. However, an increased risk for infections may be present for years and is influenced by the type of transplantation, immunosuppressive agents used, and the presence of other transplant-related complications.

Important considerations regarding infections after transplantation include:

●Immune reconstitution is slower after allogeneic HCT and is especially prolonged in recipients of human leukocyte antigen (HLA)-mismatched grafts, T cell-depleted grafts, and in the presence of cGVHD.

●HCT recipients typically lose immunity to pathogens against which they were previously immunized.

●Latent viral infections may be reactivated, and new viral infections acquired through blood transfusion.

●Asplenia, whether surgical or functional (eg, in association with cGVHD) increases the risk of infections by encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria spp, Capnocytophaga canimorsus) and by intra-erythrocytic parasites (eg, Babesia microti) in certain geographic areas. (See "Prevention of infection in patients with impaired splenic function".)

●Clinical presentations that suggest an infection may also be caused by cGVHD, lung irradiation, disease recurrence, second cancers, or other noninfectious etiologies.

Cardiovascular disease — Cardiovascular (CV) diseases are among the most common causes of morbidity and NRM in transplant survivors. Rates of CV complications vary with prior treatments, traditional CV risk factors (eg, hypertension, dyslipidemia, diabetes), and the presence of cGVHD.

The prevalence of long-term CV complications in transplantation survivors is approximately 5 percent at 5 years and 9 percent at 15 years [69-71]. CV diseases account for 2 to 11 percent of mortality among long-term transplant survivors [2,5,6]. As an example, in a single-institution study, cardiomyopathy, ischemic heart disease, all-cause CV death, and stroke were reported in 6.0, 3.8, 3.7, and 3.5 percent of survivors, respectively, at 10 years [72]. Most cases of heart failure (HF) occur within the first four years after transplantation, but HF may also present more than eight years after HCT [73]. In one study, the incidence of CV death was greater in transplant survivors than in a matched nontransplant population, while another study reported that survivors of HCT have a higher incidence of CV conditions compared with their nontransplant siblings [3,74].

Factors associated with increased CV risk in transplant survivors include:

●Increased incidence of CV risk factors – The risk for developing CV risk factors (eg, hypertension, dyslipidemia, diabetes, metabolic syndrome) is greater in transplant survivors than in the general population. A single-center retrospective study estimated the 10-year cumulative incidences of new-onset hypertension, diabetes, and dyslipidemia were 22, 10, and 31 percent, respectively, among 1885 HCT survivors who were followed for a median of 5.9 years [75]. Compared with autologous HCT, allogeneic HCT was associated with earlier development of CV risk factors and an increased likelihood of developing multiple risk factors.

One study that included both allogeneic and autologous transplantation reported that prior smoking, hypertension, dyslipidemia, diabetes, and obesity conferred additional risk for all CV outcomes (hazard ratio [HR] ≥1.5 for each additional risk factor), except for stroke [72]. In another study, modifiable risk factors including smoking, obesity, low physical activity, and a diet low in fruits and vegetables were associated with increased CV disease in transplant survivors, but healthier lifestyles attenuated the risk [76].

●Chronic GVHD – Active cGVHD and its treatment are associated with increased CV risk. In one study, compared with patients without active cGVHD, CV mortality was greater in patients with active cGVHD (HR 4.0; 95% CI 1.1-14.7) [72]. Treatments for cGVHD, including cyclosporine, tacrolimus, and glucocorticoids are associated with hypertension and may exacerbate hyperlipidemia [69,77].

●Prior cancer treatment:

•Chemotherapy – Prior chemotherapy, including anthracyclines and high dose cyclophosphamide, can lead to delayed nonischemic HF. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

•Radiation – Chest radiation prior to HCT or total body irradiation (TBI) as a component of the conditioning regimen are associated with accelerated atherosclerosis and other forms of cardiotoxicity [78]. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

●Clonal hematopoiesis of indeterminate potential (CHIP) – CHIP is associated with increased mortality from CV complications. CHIP is associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both of which are common indications for HCT, and CHIP may persist even after successful treatment of a hematopoietic neoplasm. CHIP and its association with CV complications are discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

CV disease in cancer survivors is discussed separately. (See "Cancer survivorship: Cardiovascular and respiratory issues".)

Surveillance for CV disease in transplant survivors is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Cardiovascular'.)

Pulmonary disease — Late noninfectious pulmonary complications include chronic lung allograft dysfunction (CLAD) and its two main phenotypes, CLAD-bronchiolitis obliterans syndrome and CLAD-restrictive allograft syndrome, which are manifestations of cGVHD of the lung; pulmonary hypertension; and other disorders.

Although chronic respiratory failure is more common after allogeneic HCT than autologous HCT, pulmonary complications are the most common cause of late NRM after autologous HCT [5,11]. Factors that contribute to respiratory conditions include lung injury from TBI, chemotherapy (eg, bleomycin), infections, and inflammatory pneumonitides. Pulmonary complications after autologous and allogeneic HCT and pulmonary manifestations of cGVHD are discussed separately. (See "Pulmonary complications after autologous hematopoietic cell transplantation" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Lung'.)

Monitoring the long-term survivor for pulmonary complications is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Pulmonary'.)

Liver disease — Long-term survivors of HCT are at risk for liver dysfunction due to multiple contributing factors, including:

●Chronic GVHD – Clinical effects of cGVHD on the liver are discussed separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Liver'.)

●Medications – Medications are a common cause of liver abnormalities. (See "Drug-induced liver injury".)

●Viral hepatitis – Patients with a history of infection with hepatitis B virus and hepatitis C virus (if not previously treated) are at risk for the reactivation of latent hepatitis and liver failure. (See "Overview of the management of chronic hepatitis C virus infection" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Liver histology'.)

●Iron overload – Iron overload is rare after autologous HCT but has been reported in 25 to 60 percent of patients after allogeneic HCT [79-81]. Chronic transfusional support may cause iron overload and secondary hemochromatosis, with the potential for long-term hepatic, pancreatic, gonadal, infectious, and cardiac complications [82,83]. Approximately one-third of long-term allogeneic HCT survivors have evidence of iron overload [79]. Evaluation and management of iron overload is discussed separately. (See "Approach to the patient with suspected iron overload" and "Iron chelators: Choice of agent, dosing, and adverse effects".)

Monitoring liver function in the transplant survivor is described separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Liver disease'.)

Renal dysfunction — Transplant survivors have increased rates of kidney disease, including thrombotic microangiography, drug toxicity (eg, calcineurin inhibitors), nephrotic syndrome, and membranous glomerulopathy, but estimates of the prevalence of renal dysfunction vary widely [84-86]. Risk factors for renal complications after transplantation include prior kidney disease, radiation injury, and calcineurin inhibitors (which may exacerbate hypertension and microangiopathy). Renal complications of HCT are discussed separately. (See "Kidney disease following hematopoietic cell transplantation".)

Monitoring kidney function in the transplant survivor is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Health maintenance'.)

Endocrine disorders — Endocrine complications of HCT include:

Diabetes/metabolic syndrome — The risk for diabetes and metabolic syndrome varies with the type of HCT:

●Allogeneic HCT – The prevalence of diabetes is increased three- to fourfold after allogeneic HCT; risk factors include treatment with glucocorticoids and calcineurin inhibitors for the management of cGVHD [87]. A cohort analysis reported diabetes in 30 percent of patients two years after allogeneic HCT [69]. The association of diabetes with hyperlipidemia and hypertension ("metabolic syndrome") is common after transplantation since the individual components of this syndrome share several common risk factors [88,89].

●Autologous HCT – The prevalence of diabetes is generally not increased after autologous HCT [68,87].

Monitoring for diabetes and metabolic syndrome in transplant survivors is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Diabetes/metabolic syndrome'.)

Hypothyroidism — Hypothyroidism is common after transplantation and has been reported in nearly one-third of patients by 25 years after HCT [90]. Clinical hypothyroidism can be caused by chemotherapy preparative regimens, but the incidence is much higher for regimens that include TBI [86]. In one study, the incidence of clinical hypothyroidism in patients who underwent allogeneic HCT was approximately double that of sibling controls [91].

Monitoring for hypothyroidism in transplant survivors is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Other endocrine'.)

Hypogonadism and fertility issues — Temporary or permanent hypogonadism is common after autologous and allogeneic transplantation due to active cGVHD and/or the conditioning regimen (eg, chemotherapy and/or TBI) [92-96]. Myeloablative allogeneic transplantation almost always causes permanent sterility. Changes in hormone levels may be accompanied by a loss of libido, erectile dysfunction, vaginal dryness, and dyspareunia. Causes of hypogonadism and infertility in association with HCT are discussed separately. (See "Effects of cytotoxic agents on gonadal function in adult men" and "Overview of infertility and pregnancy outcome in cancer survivors" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment" and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Ocular and genital mucosa'.)

One study reported that only four men and no women among 120 survivors of myeloablative HCT successfully conceived within 10 years of HCT [97]. Compared with 120 matched nontransplant sibling or friend controls, HCT survivors were more likely to have tried unsuccessfully to have children (12 versus 7 percent) and were more likely to investigate alternative family-building options because of infertility (22 versus 9 percent). Approximately one-half of transplant survivors <40 years old expressed concerns regarding their infertility.

Effects of HCT on sexual well-being is discussed above. (See 'Social/sexual well-being' above.)

Evaluation and management of hypogonadism and fertility in the transplant survivor are discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Other endocrine'.)

Hypoadrenalism — Adrenal insufficiency has been reported in 13 percent of patients after allogeneic HCT and 1 percent of patients after autologous HCT [68]. Chronic administration of glucocorticoids for treatment of cGVHD can suppress the hypothalamic-pituitary-adrenal function and result in adrenal insufficiency. Cautions regarding management of hypoadrenalism in the transplant survivor are discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Other endocrine'.)

Bone and joints — Late complications affecting bone include osteopenia, osteoporosis, and avascular necrosis. Patients with cGVHD are also at risk for glucocorticoid-induced myopathy, sclerotic changes in the skin and fascia that can limit joint mobility, osteopenia, and avascular necrosis of the hip or other joints [86,98-100]. (See "Glucocorticoid-induced myopathy" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Clinical manifestations' and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Sclerotic manifestations'.)

Accelerated bone loss occurs after both autologous and allogeneic HCT, and osteoporosis has been reported in up to half of transplant survivors [101-105]. Bone loss can be due to impaired calcium and vitamin D homeostasis, osteoblast and osteoclast dysfunction, hypogonadism, and post-transplant glucocorticoids (eg, in the conditioning regimen or for cGVHD) [106]. Vertebral, but not femoral, bone loss was reported to improve, at least partially, after HCT, even without specific treatment [107,108]. In one trial, 99 adults undergoing allogeneic HCT were randomly assigned to receive calcium, vitamin D, and hormone therapy, with or without six infusions of pamidronate (before and up to nine months after HCT) [109]. Patients who received pamidronate sustained less bone loss and had a trend towards fewer vertebral fractures. In a small randomized trial, zoledronic acid given immediately prior to and following allogeneic HCT was associated with improved bone mineral density at the femoral neck, in comparison with a control cohort [110]. (See "Major adverse effects of systemic glucocorticoids", section on 'Bone and muscle effects'.)

Avascular necrosis of a major joint has been reported in 4 to 19 percent of long-term survivors of HCT [86,98,107,111]. Risk factors include prolonged glucocorticoid use, male sex, and exposure to TBI [107]. Hips (80 percent), knees (10 percent), wrists, and ankles are the most commonly involved joints.

Management of bone and joint complications in the transplant survivor is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Health maintenance'.)

Dermatologic disorders — Skin is the organ that is most often involved in cGVHD. All transplant survivors are at increased risk for development of premalignant and malignant skin neoplasms [86,98,112].

Evaluation of cutaneous graft-versus-host disease (GVHD) is discussed separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)".)

Other aspects of monitoring dermatologic complications of transplantation are discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Dermatologic'.)

Oral health — Oral and dental complications are common after transplantation.

Chronic xerostomia (dry mouth) may be associated with prior chemotherapy, radiation therapy (eg, TBI in the preparative regimen, focal irradiation for lymphomas), mucosal or salivary gland cGVHD, and sclerodermatous cGVHD involving the oral aperture. All of these conditions can cause difficulty with chewing and swallowing and result in chronic malnutrition. Chronic xerostomia is also associated with accelerated dental caries, particularly along the gum line and between teeth [113,114].

Long-term survivors of allogeneic HCT have a sevenfold increased risk of developing oral cancer [115]. Persons who underwent HCT in their childhood may have additional complications with their teeth, including damaged enamel, permanent discoloration, and abnormal tooth development [86]. Squamous cell oral cancers are particularly common among patients who underwent HCT for Fanconi anemia [86].

Oral cGVHD and monitoring for oral complications of transplantation are discussed separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Mucocutaneous' and "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Oral health'.)

Ocular complications — The most common ocular complications of HCT are cataracts and chronic dry eye (keratoconjunctivitis sicca) [116-119]. Transplant-associated conditions involving the anterior and posterior chambers of the eye include uveitis, choroiditis, infectious retinitis, and retinal microvascular disease.

●Cataracts develop in nearly all patients who receive TBI in their preparative regimen [113]. There may also be an increased incidence of cataracts after non-TBI regimens, especially for those who underwent transplantation as a child [120]. (See "Cataract in adults".)

●Keratoconjunctivitis sicca is especially common in association with decreased lacrimal gland function due to cGVHD and TBI. The incidence has been reported in approximately 20 percent of patients 15 years after allogeneic HCT and may be as high as 40 percent among patients with cGVHD [86,98].

●Ischemic microvascular retinopathy (which may be manifest as cotton-wool spots or optic disc edema with or without a decrease in visual acuity) can complicate allogeneic HCT, especially in patients receiving cyclosporine for cGVHD [86].

Monitoring for ocular complications in the transplant survivor is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Ocular complications'.)

Neurocognitive health — Neurocognitive impairment may occur in transplant survivors [121,122]. Risk factors for neurocognitive impairment include transplantation in childhood, allogeneic HCT, prolonged treatment with calcineurin inhibitors, exposure to TBI, cranial irradiation, and a history of intrathecal chemotherapy [86,98,123,124].

Screening for neurologic findings after transplantation is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Neurocognitive'.)

Anxiety and depression in transplant survivors are discussed above. (See 'Anxiety/depression' above.)

Second cancers — Development of second cancers after transplantation is discussed separately. (See "Secondary cancers after hematopoietic cell transplantation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Autologous bone marrow transplant (The Basics)" and "Patient education: Allogeneic bone marrow transplant (The Basics)")

●Beyond the basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY

●Description – Hematopoietic cell transplantation (HCT) can cure a variety of malignant and nonmalignant disorders, but it is associated with substantial toxicity. Even patients who are cured of their underlying disease may not achieve full restoration of health after HCT.

●Survival – The most common cause of death in transplant survivors is recurrence of the underlying disease. (See 'Survival' above.)

Causes of nonrelapse mortality include infection, second cancers, and organ system dysfunction. Survival patterns after transplantation are influenced by whether the patient undergoes allogeneic or autologous HCT and the underlying disease.

●Early complications – Early complications of HCT, which are manifest in the first year after transplantation, are described separately. (See "Early complications of hematopoietic cell transplantation".)

●Late complications – Late complications of HCT (ie, conditions encountered more than one year after transplantation) can affect nearly any organ system. (See 'Late complications' above.)

Factors that contribute to late complications after HCT include the underlying illness, comorbid medical conditions, aspects of the transplantation, and early complications. (See 'Contributing factors' above.)

●Quality of life – Quality of life is a multidimensional concept that includes the individual's perception of function, independence and financial well-being, psychological state, and social and sexual satisfaction. Most transplant survivors resume routine activities over time, but functional limitations and symptoms (especially fatigue) affect a significant proportion of long-term survivors. (See 'Quality of life' above.)