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 cancers. Secondary cancers are now being increasingly recognized as a complication among HSCT recipients. The magnitude of risk of secondary malignancies after HSCT has been found to be increased four‐fold to 11‐fold compared to the general population. The estimated actuarial incidence is reported to be about 3–4% at 10 years, increasing to 10–12 % at 15 years after allogeneic HSCT [13, 14, 49‐53].
Risk factors for the development of secondary malignancies include exposure to chemotherapy and radiation before transplantation, use of TBI and high‐dose chemotherapy used in preparation for HSCT, infection with viruses such as Ebstein‐Barr virus (EBV) and Hepatitis B and C viruses (HBV and HCV), immunodeficiency after transplant, aggravated by the use of immunosuppressive drugs for prophylaxis and treatment of GVHD, including the use of monoclonal and polyclonal antibodies, HLA non‐identity, and T‐cell depletion, the type of transplant (autologous versus allogeneic), the source of hematopoietic stem cells used, and the primary malignancy. However, assessment of risk factors for all secondary malignancies in aggregate is somewhat artificial because of the heterogeneous nature of the secondary malignancies, with differing clinico‐pathological features, distinct pathogenesis, and hence very distinct risk factors associated with their development [13, 14].
Currently secondary malignancies after HSCT are categorized into three distinct groups: 1) myelodysplasia and acute myeloid leukemia, 2) lymphoma, including lymphoproliferative disorders and 3) solid tumors.
Secondary leukemia after allogeneic HSCT
Secondary leukemia in the setting of allogeneic HSCT refers to leukemia of donor cell origin or a new leukemia developing in surviving patient cells. Both are extremely rare complications, raising important questions on leukemogenesis. Recently, the Seattle team has suggested that transfer with the donor graft of otherwise silent malignant cells could also be responsible for leukemias arising from donor cells. However, no clear evidence links these secondary leukemias to cGVHD. Nevertheless, with increasing use of older donors (especially for patients receiving reduced intensity conditioning) special attention must be given to the search for hematological abnormalities in the donor and of clear need for donor’s surveillance.
The development of new leukemias in patient cells is most likely related to cytotoxic conditioning therapy; there is no evidence to support a role of cGVHD.
Lymphomas
Posttransplant lymphoproliferative disorders (PTLD) are the most common secondary malignancy in the first year after allogeneic HSCT. Most of these cases are related to compromise immune function and Epstein‐Barr virus (EBV) reactivation. The large majority of the PTLD have a B‐cell origin, though some T‐cell PTLDs have been described [54, 55].
Nevertheless, several cases of late‐occurring lymphomas have been reported in the literature. It is believed that these late‐occurring lymphomas represent an entity that is distinct from the early‐occurring B‐cell PTLD [56–59].
“Secondary” Hodgkin disease (HD) has also been observed among HSCT recipients. HSCT recipients followed as part of a large cohort study were at a six‐fold increased risk of developing HD when compared with the general population [60]. Most of the reported cases were of the mixed cellularity subtype, and most of these cases contained the EBV genome. These cases differed from the EBV‐associated PTLD by the absence of risk factors commonly associated with EBV‐associated PTLD, by a later onset (>2.5 years), and relatively good prognosis. The increased incidence of HD among HSCT recipients could possibly be explained by exposure to EBV and over‐stimulation of cell‐mediated immunity, but no clear evidence for a link with cGVHD has been established.
Solid Tumors[53]
Solid tumors have been described after syngeneic, allogeneic and autologous HSCT. The increase in the risk of solid tumors has ranged from 2.1‐fold to 2.7‐fold when compared to an age‐ and sex‐matched general population [61, 62]. The risk increased with increasing follow‐up, and, among those who survived 10 or more years after transplantation, was reported to be 8.3 times as high as expected in the general population. Types of solid tumors reported in excess among HSCT recipients, were those typically associated with exposure to radiation therapy, including melanoma, squamous cell carcinomas of the oral cavity and salivary glands, and cancers of the brain, liver, uterine cervix, thyroid, and breast, as well as sarcomas of the bone and connective tissues.
Pathogenesis
Little is known about the pathogenesis of solid tumors. An interaction of cytotoxic therapy, genetic predisposition, viral infection, and GvHD with the resulting antigenic stimulation and the use of immunosuppressive therapy, all appear to play a role in the development of new solid tumors [63,64].
Radiation‐related cancers generally have a long latency period, and the risk of such cancers is particularly high among patients undergoing irradiation at a young age. A large series reported an increased risk of brain and thyroid cancers after TBI given as part of myeloablative conditioning, though most of these patients had also received cranial irradiation prior to HSCT. Both thyroid cancer and brain tumors have been