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Large numbers of patients now survive long‐term following hematopoietic stem cell transplantation (HSCT), and late clinical effects of HSCT are, thus, of major concern. Chronic graft‐versus‐host disease (cGVHD), and the associated immunodeficiency are the primary causes of transplant‐related mortality late after allogeneic HSCT and contribute directly or indirectly to most late complications. Despite the advent of new treatment modalities the incidence of cGVHD has remained high, related to several changes in clinical HSCT practice: (i) the expanded use of HLA matched unrelated and HLA non‐identical related donors; (ii) the increasing use of HSCT in older patients; (iii) the increasing use of viable donor lymphocyte infusions after HSCT to treat relapsed disease or to achieve full donor chimerism after non‐myeloablative transplantation; (iv) the increasing use of peripheral blood stem cells instead of bone marrow as a source of stem cells. In addition to cGVHD and its therapy, the major risk factor for late complications after HSCT is the use of irradiation in the pretransplant conditioning regimen.

cGVHD — which was originally defined as occurring after the first 100 days post‐HSCT — is now known to have a characteristic clinical presentation, which resembles autoimmune vascular diseases and is distinct from that of acute GvHD [1–5]. cGVHD occurs in 30–65% of allogeneic HSCT recipients, can be highly debilitating in its extensive form and has a 5‐year mortality rate of 30–50% that is mainly due to immune dysregulation and opportunistic infections. The pathophysiology of cGVHD mainly depends on the polarization of CD4+ T cells into T‐helper 2 (TH2) cells, but there are six hallmarks that are unique to this syndrome (reviewed in Zeiser and Blazer [5]; Blazer et al. [6]. The first feature is damage to the thymus (a), which can be caused by the conditioning regimen or, more importantly, by prior occurrence of acute GvHD. This damage results in decreased negative selection of alloreactive CD4+ T cells (b). There is immune deviation to a TH2‐type cytokine response (c), which includes the production of interleukin‐4 (IL‐4), IL‐5 and IL‐11. This response leads to the release of fibrogenic cytokines — such as IL‐2, IL‐10 and transforming growth factor‐β1 (TGFβ1) — and the activation of macrophages that produce platelet‐derived growth factor (PDGF) and TGFβ1 (d). These molecules induce the proliferation and activation of tissue fibroblasts. Low numbers of regulatory T (Treg) cells are the fifth hallmark (e), and finally there is B cell dysregulation (f), which leads to the emergence of autoreactive B cells and the production of autoreactive antibodies. It has been suggested that autoreactive B cell activation may be due to the presence of high levels of B cell‐activating factor (BAFF) in the lymphoid microenvironment. All these events contribute to an autoimmune‐like systemic syndrome that is associated with fibroproliferative changes. These changes can occur in almost any organ of the body but mainly affect oral and ocular mucosal surfaces and the skin, lungs, kidneys, liver and gut.

Immune reconstitution occurs gradually over time (generally 12–24 months) and is slower for allogeneic recipients, particularly those receiving umbilical cord blood, HLA‐mismatched or T‐cell depleted grafts and in survivors with GVHD or those who have received prolonged immunosuppression [7,8]. T‐helper lymphocyte (CD4) counts and CD4/CD8 ratios are good markers of immune reconstitution and some experts use these assessments as surrogate markers of the completeness of immune reconstitution to guide duration of viral or other infection prophylaxis after HSCT. Immune reconstitution has a pivotal role in the long‐term issue of allogeneic HSCT. cGVHD is the major factor affecting immune reconstitution of B cells and CD4‐ and CD8‐T cells [9,10]. Donor source (marrow versus peripheral blood), unrelated versus sibling transplant, and the degree of HLA‐compatibility between donor and recipient also affect the pace of immune reconstitution. Low B‐cell count, inverted CD4/CD8 ratio and a decreased IgA level are all risk factors associated with late infections [11]. Susceptibility to encapsulated bacteria (S. pneumoniae, H. Influenzae, and N. Meningitis) has been well documented, especially in patients with current or previous cGVHD. Late (> 2 years) fungal or CMV infections are rare, and almost invariably occur in patients with ongoing immune suppression for GVHD. Varicella zoster in contrast, is extremely frequent even in patients without GVHD, but usually occurs within several months of HSCT after acyclovir prophylaxis has been discontinued. Finally, late Pneumocystis carinii (PCP) infections are more common in patients receiving active treatment for cGVHD. Since PCP prophylaxis with trimethoprim‐sulfamethoxazole is highly active, this regimen should be given to all patients receiving treatment for cGVHD and/or those with CD4‐positive cells < 0.2 x10⁹/L. Probably, PCP prophylaxis should be continued for several weeks after the cessation of immunosuppressive therapy given the long‐lasting T‐cell defects characteristic of patients who have developed cGVHD. Guidelines for preventing infectious complications among HSCT recipients have also been extensively reviewed [12].

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.