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.
Identification of late effects
Various methods of identifying late effects can be utilized. Unfortunately, since many organs or organ systems can be involved simultaneously, a strict timeline for the preventive landmarks post‐HCT cannot be formulated. Very late effects can be defined as those occurring at least 5 years post‐HCT. A general guidance strategy for psychological and organ‐based aspects of late effects is delineated. The common non‐relapse late effects occurring after HCTs are depicted in Table 6.1 and a brief description of each complication is given in this chapter.
Late effects
Acute and chronic infections
Infections occurring late in allogeneic‐HCT recipients typically have an onset within the first year of transplant, but HCT recipients remain at risk for a long period, especially when being treated with IST for cGVHD. After an allogeneic‐HCT, it may take a few months or up to one year for the immune system to completely reconstitute, thus justifying scheduled re‐vaccinations at regular intervals late after transplant, as indicated per the current immunization guidelines unless treatment for GVHD is ongoing. Owing to both IST and cGVHD, immune recovery can be delayed and a functional immunodeficiency state can persist post‐transplant beyond one year due to impairment of both humoral and cell‐mediated immunity (mainly due to persistent lymphopenia), decreased opsonization, and hyposplenism in certain cases. The risks of acute infections are heightened by mucocutaneous damage, which occurs due to skin, oral, and gastrointestinal (GI) cGVHD, and due to iatrogenic reasons (e.g., intravenous [IV] catheters for extracorporeal photophoresis). Extra care should be taken to examine the catheter sites, and for surveillance of skin or oral mucosal tears due to cGVHD.
Among the late viral infections, Epstein–Barr virus is exceedingly common, but infrequently causes any permanent late sequelae (except posttransplant lymphoproliferative disorder, as discussed later) Varicella zoster virus (VZV) and cytomegalovirus (CMV) are the most common organisms causing complications. The VZV‐mediated infections typically occur during the first 6–12 months post‐HCT (approximately 80% of cases) [12]; the disseminated disease is much more common in allogeneic‐HCTs than in autologous HCTs (45% versus 25%) and the lesions are likely to last longer and heal more slowly than in normal adults [13], necessitating the need for prophylactic therapy with anti‐VZV drugs for a long period even in the absence of cGVHD. Herpes simplex encephalitis, JC/BK infections, hepatitis B and C virus infections and reactivations, and HIV infection are rare late effects and do not necessarily need long‐term surveillance.
Human herpesvirus 6 (HHV‐6) infections occurring after HCT deserve special attention as significant late morbidity and mortality can be associated with this infection [15]. HHV‐6 infection can lead to memory loss, insomnia, confusion, hyperintense signals of the hippocampi on brain magnetic resonance imaging, and temporal lobe seizure activity on electroencephalography [14]. Since similar symptoms may occur in acute meningitis and some cases of calcineurin inhibitor (CNI)‐associated encephalopathy, a high level of suspicion for HHV‐6 encephalitis is required to send the appropriate diagnostic tests for this condition.
Late‐onset fungal infections include candida species, invasive aspergillosis, Fusarium species, and the Zygomycetes. They are more common within a few months of allogeneic‐HCTs and do not require surveillance besides a heightened awareness and prompt diagnostic testing in symptomatic patients for urgent treatment, particularly in high‐risk patients such as cGVHD patients on high‐dose corticosteroids.
Table 6.1 Non‐relapse late and very late effects after allogeneic HCT
| Late effect | Incidence | Risk factor | Surveillance/screening | Preventable | Treatable |
|---|---|---|---|---|---|
| 1. Acute and chronic infections | ++ | Prolonged immunosuppression, steroids | CT, PCR, serum test | Yes | Yes |
| 2. Cutaneous complications | +++ | GVHD | Dermatology exam yearly | No | Yes |
| 3. Oral/dental complications | ++ | GVHD | Oral exam yearly | No | Yes |
| 4. Hepatic complications | + | HBV, HCV, complementary and alternative medicine, iron overload | T.bil, ALT, US, HBV/HCV viral load, ferritin, T2* MRI, FerriScan, SQUID | No/Yes | Yes/No |
| 5. GI complications | + | GVHD, steroids, mychophenolate mofetil | Endoscopy | No | Yes |
| 6. Genital complications |
+
|