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 surveillance strategies for early recognition and prompt management of these late effects are best undertaken in multidisciplinary long‐term follow‐up. Future allogeneic HCT studies should focus on assessing long‐term outcomes by obtaining pretransplant risk factors for late effects, translational studies utilizing biomarkers, and follow‐through of the late and very late complications in a prospective fashion.
Summary
Introduction: Significant advancements in the supportive care and better conditioning regimens have led to improved survival in HCT recipients. Concurrently, an increase in the late complications have been observed in these groups compared to controls. Late effects affect almost every organ and lead to both morbidity and mortality in the HCT survivors.
Risk factors of the effects: Both clinical and genetic risk factors play a role in the development of late effects in HCT survivors. Among clinical risk factors, receipt of irradiation, certain chemotherapies (e.g. cyclophosphamide) and lifestyle factors (e.g. smoking, alcohol intake), significantly increase the risk of both cardiovascular complications and subsequent cancers. GVHD and its associated treatments (immunosuppressants) also contribute to the risk of many late effects. Among inherited risks, a genetic predisposition to enhanced toxicity (e.g. cardiotoxicity due to anthracyclines) and inherited DNA defects leading to increases in oral carcinomas in Fanconi Anemia are some examples.
Late effects: Late effects in HCT survivors may include acute and chronic infections (including HHV6, fungal and mycobacterial infections), cutaneous complications (e.g. vitiligo, carcinomas), oral cavity complications (particularly squamous cell carcinomas), hepatic complications (including cirrhosis), GI complications (e.g. malnutrition), genital complications (vaginal stenosis, phimosis etc.), renal complications (leading to chronic kidney disease), ocular complications (e.g. retinopathies, dry eye syndrome etc.), endocrine complications (diabetes and hypothyroidism), hypogonadism, fertility loss, dental complications, musculoskeletal and bone complications (including avascular necrosis and contractures), pulmonary complications (including BOS), neurologic complications (neuropathies, strokes), psychological and social complications (including financial toxicity and PTSD), sexual dysfunction, cardiovascular complications (particularly ischemic heart disease and HTN), subsequent solid malignancies, and subsequent hematologic malignancies.
Future directions: Existence of multidisciplinary clinics for the early detection and comprehensive management of these late effects is warranted given their effect on mortality and morbidity. Prospective studies with translational elements (e.g. biomarker discovery, metabolomics, microbiome assessments, etc.) are urgently needed for these HCT survivors.
References
