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 (men) alone. In a retrospective study of pediatric HSCT recipients, treatment with bisphosphonates was well tolerated and was associated with improvement in BMD [45]. Preventive measures of bone loss after HSCT are indicated. Many experts recommend the use of anti‐resorptive treatments (gonadal hormonal replacement or bisphosphonates) in patients with gonadal failure and with cGVHD requiring treatment with glucocorticoid [46]. Hormone replacement after HCT should be individualized with the pros and cons discussed carefully with each patient before initiation of replacement and reassessed at least yearly if treatment is continued beyond 1–3 years after HCT. Increased risk of breast cancer, coronary heart disease (CHD), stroke, and venous thromboembolism was reported in the Women's Health Initiative (WHI) study (non‐transplanted women older than 50 years) with continuous combined estrogen‐progestin replacement versus placebo, for an average of 5.2 years. Nonetheless, this study also showed a significantly reduced risk of bone fractures and colon cancer [47].
Late cardiovascular complications [48]
Cardiovascular disease is caused by disorders of blood vessels and is closely related to atherosclerosis. Atherosclerosis is now considered an inflammatory process, where endothelial lesions occur decades before clinical manifestations such as stroke, coronary heart disease or peripheral arterial disease become manifest. Based on such concepts, cardiovascular disease might be expected decades after an endothelial damage occurs. Risk factors for arteriosclerosis in the general population are well established, and include smoking, arterial hypertension, obesity, diabetes, dyslipidaemias and physical inactivity. After HSCT, endothelial damage is induced by the conditioning regimen, and endothelial cells have been documented as a target of GVHD. In addition, a higher incidence and degree of cardiovascular risk factors might be the result of post‐transplant endocrine dysfunction, prolonged treatment with immunosuppressive drugs, or sedentary lifestyle. The increased incidence of cardiovascular events after allogeneic HCT supports the hypothesis that GVHD could be involved in the process. This is in line with the data on rarefaction of micro vessels in patients with cGVHD. This loss of micro vessels in the skin in cGVHD takes place independently of the epidermal injury. Patients with cGVHD have a significantly lower micro vessel density in the subcutaneous compartment, as compared to healthy controls. The correlation between GVHD and endothelial injury is also suggested in a study where donor‐derived cells contributed to the endothelial repair of GVHD‐induced lesions. Endothelial injury, due to a persistent vascular inflammation and endothelial cell death provoked by GVHD could therefore be responsible for atherosclerosis, and lead to premature cardiovascular accidents in long‐term survivors after allogeneic HSCT. Because of the long latency between an initial vascular injury and the appearance of a cardiovascular event, symptomatic cardiovascular disease might appear only decades after transplantation.
Secondary Malignancies
Secondary malignancies are a known complication of conventional chemotherapy and radiation treatment for patients with a variety of primary
