Osteopenia and avascular necrosis (AVN) of the hip or other joints are well described late bone effects of HCT which may occur as a result of corticosteroid therapy for GVHD [45]. AVN occurs frequently post‐HCT, and about 4–10% of the patients may be affected with at least one joint with AVN [46]. Vitamin D, plus calcium supplementation and annual dual‐energy X‐ray absorptiometry scans, for bone health are described in detail in Chapter 15.
Common late musculoskeletal effects include steroid‐induced myopathy, fasciitis/scleroderma, and polymyositis, and up to one‐third of patients may report musculoskeletal symptoms even after 10 years of HCT [47]. Sclerosis as a manifestation of cGVHD can affect the skin and subcutaneous tissues, including fasciae and joints. Prompt recognition of these complications by clinical examinations, serology, and neurologic studies and early intervention may prevent permanent disability.
Pulmonary complications
Infections (particularly aspergillosis, HHV‐6, CMV, respiratory syncytial virus, influenza, and parainfluenza viruses), BOS (bronchiolitis obliterans syndrome), COP (cryptogenic organizing pneumonia) and pulmonary thromboembolism are the main pulmonary late effects of allogeneic‐HCT. BOS occurs in 2–14% of allogeneic‐HCT recipients [48]. Smoking, TBI, chemotherapy (particularly busulfan), preexisting lung disease, and early HCT pulmonary complications are known risk factors. Surveillance strategies with history, examinations and pulmonary function tests at regular intervals post‐HCT may help to diagnose BOS in its early stage. This topic is further discussed elsewhere.
Neurologic complications
Late neurologic effects include neurocognitive defects, neuropathy, central nervous system (CNS) GVHD, and CNS infections. Neurocognitive impairment after allogeneic‐HCT is common, and up to 40% of the HCT survivors may exhibit cognitive deficits even five years post‐HCT [49, 78]. Neuropathy in HCT survivors is highly prevalent and frequently is a result of pre‐HCT chemotherapies. CNS GVHD is an understudied area, but evidence indicating specific inflammatory GVHD changes in the brain is accumulating [50, 51], and its diagnosis requires an aggressive approach with brain biopsy since cerebrospinal fluid (CSF) analysis and brain magnetic resonance images cannot differentiate CNS GVHD from other causes. CNS infections include HHV‐6 and CMV encephalitis (see “1. Acute and chronic infections”) besides the common microbial causes of meningitis. Myasthenia gravis and demyelinating diseases, including Guillain–Barré syndrome, are rare complications. Progressive multifocal encephalopathy should also be considered in the differential diagnosis of encephalopathies if rituximab was given pre‐HCT, or for treatment of cGVHD.
Psychological and social complications
The HCT survivors and their caregivers are at a significant risk of psychological disorders [52]. Multiple factors may be responsible for this including pretransplant psychological diagnosis or spiritual absence [53], GVHD, or disease relapse. Major depression, adjustment disorders, and anxiety disorders are the most common psychiatric diagnoses in these patients. Compared with their siblings, allogeneic‐HCT survivors are less likely to continue jobs or be married and are more likely to report difficulty maintaining health insurance or acquiring life insurance [54, 55]. Late psychological effects of HCTs culminate when the psychological health of spouses/partners is affected by the HCT [56]. Thus, screening for the disorders affecting these psychological and social domains at regular intervals is suggested and described in detail in Chapters 34–36.
Sexual dysfunction
Sexual late effects of allogeneic‐HCT occur in a significant number of survivors and are usually multifactorial in origin, with common etiologies being vulvar–vaginal GVHD, gonadal deficiencies, and depression, as discussed earlier. Detailed management is discussed elsewhere in this book.
Subsequent hematologic malignancies
This late effect usually develops within a few years of allogeneic‐HCT, but it may occur after 5 years of HCT. Donor‐derived leukemia is a well‐recognized entity [68, 69] along with post‐transplant lymphoproliferative disease [70, 71]. An aggressive diagnostic approach is mandated when leukemia or posttransplant lymphoproliferative disease is suspected late in allogeneic‐HCTs.
Very late effects
Cardiovascular complications
About one‐third of HCT patients are at increased risk of developing known cardiovascular risk factors (CVRFs) [57]. Acute GVHD and TBI have been reported to be risk factors specific to HCT along with the well‐recognized cardiotoxic chemotherapies (cyclophosphamide, anthracyclines, trastuzumab, etc.) and mediastinal radiation. The estimated prevalence of long‐term cardiovascular complications has been reported to be approximately 5% at 5 years and 9% at 15 years [41, 58]. cGVHD uniquely poses a significantly increased risk for the development of CVRFs due to the toxicity of drugs. Corticosteroids and CNI increase the risk of both diabetes and hypertension, whereas sirolimus increases the risks of dyslipidemias. CVRFs should be minimized with aggressive treatment strategies and with modification of preventable CVRFs (e.g., smoking, unhealthy diets). A recent study identified CELF4 polymorphisms associated with anthracycline‐related cardiomyopathy [72]. Routine post‐HCT care should incorporate measurements of blood pressure, nutritional counseling, obesity control, counseling for smoking cessation, and control of diabetes. Electrocardiogram/ echocardiography performance at yearly intervals may be necessary for high‐risk patients (e.g., those with CVRFs or anthracycline exposures).
Subsequent neoplasms
Allogeneic‐HCT recipients have a two‐ to threefold increased risk of developing this very late effect [59, 79]. Solid malignancies are the fourth leading cause of mortality in patients surviving more than 2 years post‐HCT. The pattern of increase is linear over time: 1.2–1.6% at 5 years, 2.2–6.1% at 10 years, and 3.8–14.9% at 15 years [60–63]. Certain conditions significantly increase the risk, particularly Fanconi anemia in which routine surveillance strategies for head/neck cancers should be utilized. Common solid cancers seen in allogeneic‐HCT survivors include thyroid, skin, oropharyngeal, and breast cancers.
Thyroid cancer is the fastest‐growing non‐skin cancer in the USA [64], and its incidence is even higher in HCT recipients. A study from the EBMT Late‐Effects Working Party suggested a threefold higher incidence of thyroid cancer in HCT recipients than in the general population [65]. TBI, female gender, and cGVHD were found to be risk factors. A vigilant clinical exam of the thyroid gland and cervical nodes at yearly intervals is recommended.
Skin cancers are the most common solid malignancies post‐HCT. In a large series, the 20‐year cumulative incidences of basal cell and squamous cell cancers were reported to be 6.5% and 3.4%, respectively [66]. TBI and GVHD were found to be risk factors. An annual dermatologic examination for skin cancer screening is recommended.
Breast cancer risk is elevated among HCT recipients, with a reported cumulative incidence of 11% at 25 years post‐HCT [67]. Risk factors include TBI and prior chemotherapies. Annual mammography is recommended.
Future directions
Many novel developments in management or prognostication of late effects of HCT have occurred, most notably of which include machine learning methods for GVHD predictions [72], inheritable risk for cardiotoxicity [73], and the effect of microbiome on late infectious complications [74].
With the improvement in the survival of allogeneic‐HCT patients [75], it is predicted that more late complications will be identified in the HCT recipients. Evidence‐based