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Advances in allogeneic hematopoietic cell transplantation (HCT) have increased the curative potential of the procedure and HCT survivors are living longer, however, at a cost of a higher burden of late complications (also known as “late effects”). The late effects have traditionally been defined as the complications arising at least six months after [1], and include both relapse and non‐relapse complications. Though the relapse incidence is highest early after HCT, most recipients remain at risk for relapse beyond one year following HCT [2] and support the use of an intense monitoring program for high‐risk patients with disease‐specific morphologic, radiologic, and/or molecular parameters. Since patients with relapsed disease are treated with intensive therapies, they are conventionally excluded from the general management model of a typical long‐term follow‐up, as discussed in detail elsewhere in this book. The basic concepts of non‐relapse late effects, including the role of chronic graft‐versus‐host disease (cGVHD) in late effects, are discussed in this chapter. The details of management for individual late effects are described later in the book. Details of cGVHD and its management are also described elsewhere.

Most of the late effects can be categorized based on the organ or system‐specific complications and usually arise due to a complex interaction of various factors which may include:

1 Chemotherapy/radiotherapy‐ or immunosuppressive therapy (IST)‐related complications (e.g., increased risk of subsequent cancers or increased risk of diabetes)

2 Direct effect of cGVHD (e.g., dry eye or dry mouth resulting from cGVHD)

3 Pretransplant co‐morbidities (e.g., a high HCT‐CI score)

4 Genetic predisposition to enhanced toxicities. (e.g., the presence of certain polymorphisms can predict late cardiotoxicity).

The complications arising from either of these variables may coalesce to decrease both the survival and the quality of life (QoL), (see Figure 6.1) thus making the biologic plausibility of a particular outcome with causation very difficult. An example of such an interaction in post‐HCT patients is fertility loss, which is a well‐known phenomenon in the survivors of HCT [3] and is associated with total body irradiation (TBI) due to endocrine disruption (central or gonadal) [4,5]. cGVHD may also lead to unsuccessful conception due to anatomic complications, especially when vaginal stenosis or strictures develop [6]. Among the baseline health parameters, smoking has an established relationship with fertility loss [7] (though data are lacking regarding this association within the HCT literature). Thus, various factors combine to cause adverse outcomes in an allogeneic HCT survivor.

Certain late effects of allogeneic HCTs are likely underestimated owing to the long time of occurrence of these effects. Since the probability of being lost to follow‐up is increasing by years after HCT [8], the data for the incidence of very late complications (e.g., subsequent neoplasms and cardiovascular effects) may not be appropriately captured and thus may lead to an underestimation of the true incidence.

The late effects of cGVHD occur in a nonsystematic fashion. Once cGVHD starts to manifest in a particular organ or system, quite frequently other organs/systems may also show signs of involvement with cGVHD, leading to autoimmune‐like systemic syndrome [9]. However, histologic and immunologic studies indicate a wide variety of differences in pathologic manifestations among different organs involved with cGVHD; for example, in liver cGVHD, the biopsies have indicated the presence of lobular hepatitis and a reduction or absence of small bile ducts with cholestasis resembling primary biliary cirrhosis [10], whereas, in cutaneous cGVHD, epidermal atrophy and dense focal dermal fibrosis are apparent without any significant inflammation [11]. Furthermore, specific organ late effects thought to occur only from cGVHD may have other etiologic factors playing a role. In summary, the exact pathogenesis of the late effects manifested as organ‐specific cGVHD are complex and a detailed discussion of this issue is beyond the scope of this chapter.

Figure 6.1 Dynamics of etiology of late effects in allogeneic HCT survivors.