Extensive reviews with references have been published [13–16] thus, only selected references are included in this chapter. Since most chapters in this book also refer to the relationship between cGVHD and late effect, only main concepts will be reviewed in two different sections:
Non‐malignant late effects which are heterogeneous, and though often non‐life threatening, significantly impair the quality of life of long‐term survivors [17].
Secondary malignant diseases which are of particular clinical concern as more patients survive the early phase after HSCT and remain free of their original disease [13, 14] and the authors review in this book.
cGVHD and nonmalignant late effects
Ocular effects [18]
Kerato‐conjunctivitis sicca and cataracts are the two most common late complications affecting the anterior segment of the eye.
Cataract formation, particularly posterior sub‐capsular cataracts, has long been recognized in recipients of hematopoietic HSCT [19, 20]. The two main risk factors for cataract development are exposure to TBI and steroids therapy for cGVHD [19–21]. After single‐dose TBI, almost all patients developed cataracts within 3 to 4 years, and most, if not all, need surgical repair. The probability of developing cataracts after fractionated TBI is in the range of 30% at 3 years, but may be as high as 80% at 6 to 10 years after HSCT. In a multivariate analysis, the use of TBI, single as compared to fractionated dose TBI, and the use of steroid treatment for longer than 3 months were associated with a significantly increased risk of cataract development [21]. The radiation effect was dose‐rate dependent [22,23]. The largest series to date included a cohort of 1064 patients and identified as factors independently associated with an increased risk of cataracts; older age (>23 years), higher radiation exposure rate (>4 cGy/min), allogeneic rather than autologous HSCT, and steroid administration [22,23]. Finally, in prospective studies comparing the incidence of cataracts and predisposing risk factors, patients who received cyclophosphamide and TBI (Cy/TBI) had a higher incidence of cataracts than patients treated with busulfan and Cy (Bu/Cy) [24].
Kerato‐conjunctivitis sicca of the eyes is usually part of a more general syndrome that also includes xerostomia, dryness of the skin, and, in women, vaginitis. All these manifestations are closely related to cGVHD [25–28]. In its most extensive form, the clinical picture may be that of a Sjögren‐like syndrome, as described in detail in other chapters of this book.
Pulmonary effects [29,30]
Significant late toxicity involving both the airways and the lung parenchyma is observed in at least 15% to 40% of patients after HSCT [17, 31‐33]. Most studies have been performed in adult patients and results are still conflicting, due to differences in patient selection and evaluation criteria, limited sample size, and short follow‐up. Moreover, the various pulmonary syndromes are not well defined or definable because of overlapping mechanisms and because they represent a continuous spectrum rather than distinct disorders. Sensitivity to cytotoxic agents and irradiation, infections, and immune‐mediated lung injury associated with GVHD are the most prominent factors, which contribute to late respiratory complications. Impaired growth of both lungs and chest wall can be additional factors in patients who are transplanted as young children.
Restrictive lung disease
Restrictive lung disease is frequently observed 3 to 6 months after HSCT in patients conditioned with TBI and receiving an allogeneic HSCT but, in most cases, it is not symptomatic. Restrictive disease is often stable and, in fact, may resolve, partially or completely, within 2 years of HSCT. However, some patients do develop severe late restrictive defects and may eventually die from respiratory failure [31,34].
Chronic obstructive lung disease
Chronic obstructive pulmonary disease (COPD) with reduced FEV1/FVC and FEV1 develops in up to 20% of long‐term survivors after HSCT. The pathogenesis is not well understood, but cGVHD, TBI, hypo‐gammaglobulinemia, GVHD prophylaxis with methotrexate, and infections have been described as risk factors [17] and review in Barker et al. [35].
Complications of bones and joints [36]
Avascular necrosis of bone (AVN)
The incidence of AVN has been reported at 4% to more than 10%. The mean time from transplant to the diagnosis of AVN is 18 months, and joint pain is usually the first sign [37–40]. The hip joint is affected in more than 80% of cases with bilateral involvement occurring in more than 60% of cases. Other locations described include the knee (10% of patient with AVN), wrist and ankle. Symptomatic relief of pain and orthopedic measures to decrease the pressure on the affected joints are of value, but most adult patients with advanced damage will require surgery. By 5 years, about 80% of patients will have undergone total hip replacement. Short‐term results of joint replacement are excellent in more than >85%, but further long term follow‐up is required, particularly in young patients, to determine outcome over an extended life span [41]. Steroid use (both total dose and duration) is the strongest risk factor for AVN [37‐41,42].
Osteoporosis
Hematopoietic HSCT can induce bone loss and osteoporosis via the toxic effects of TBI, chemotherapy, iatrogenic hypogonadism and may be compounded by prolonged inactivity of patients after HSCT [43, 44]. Osteopenia and osteoporosis are characterized by a reduced bone mass and increased susceptibility to bone fracture. These conditions are distinguished by the degree of reduction in bone mass and can be quantified on dual energy X‐ray absorptiometry. The cumulative dose and number of days of glucocorticoid therapy, and the number of days of cyclosporine or tacrolimus therapy showed significant associations with loss of bone mass. Non‐traumatic fractures occurred in 10% of patients. Using WHO criteria, nearly 50% of patients after HSCT have low bone density, one third have osteopenia and approximately 10% have osteoporosis by 12–18 months after HSCT.
Few studies on the safety and efficacy of bisphosphonate for prevention of bone loss after HSCT have been reported. Results of a randomized study in adult allogeneic HSCT recipients showed less bone loss in patients receiving additional pamidronate (60 mg before and 1, 2, 3, 6, and 9 months after HSCT) compared to patients receiving 1000 mg calcium carbonate and 800 IU vitamin D daily, and estrogen (women) or testosterone