males, penile cGVHD is the most frequent genital late effect, which can result in Peyronie’s disease or phimosis [35].
Annual comprehensive dermatologic evaluations in both men and women should include complete genital assessments for genital cancers and cGVHD screening. The 2014 NIH cGVHD scoring system has been updated to reflect the complications in male genital tract [36].
Renal complications
The use of prior nephrotoxic medications (e.g., cisplatin, foscavir, vancomycin etc.) and CNI therapy for the prevention or treatment of GVHD predisposes to the development of chronic kidney disease [37] which can manifest as either glomerulonephritis or interstitial fibrosis. Among chronic infections, CMV and adenovirus are known offenders, and a search for these organisms is warranted if renal infections are suspected.
Ocular complications
Ocular cGVHD commonly results in decreased lacrimal gland function, resulting in chronic dry eye (keratoconjunctivitis sicca) as the main late effect and its incidence may be up to 40% among patients with cGVHD [76]. Tear production can be measured with the Schirmer test but since this may be technically challenging to transplant clinicians, it is no longer an absolute requirement for organ severity scores of cGVHD as per the 2014 NIH cGVHD criteria. Non‐cGVHD ocular complications include cataracts, ischemic retinopathy, and infections. Cumulative incidence of cataracts in children has been reported to be 36% at 15 years post‐HCT [38]. Though TBI has a strong association with cataracts, many patients remain at risk for cataract due to chronic corticosteroid therapy for cGVHD. Ischemic retinopathy is an uncommon complication but has been described in HCT settings, particularly in the setting of systemic cyclosporine use.
Since complete vision loss impairs QoL of long‐term HCT survivors more than any other organ complication, HCT recipients must have ophthalmologic examinations at regular intervals. Detailed management of ocular complications is given in Chapter 16.
Endocrine complications
Late endocrine effects of allogeneic‐HCT usually occur as a result of radiation, chemotherapy, or due to cGVHD treatments [39, 77]. Organs commonly involved include the thyroid gland, gonads, and pancreatic islets. Despite frequent exposures to corticosteroid therapies, the HCT recipients generally have a low incidence of hypoadrenalism. The major risk factor for hypothyroidism is TBI. The median time of occurrence of hypothyroidism is 4 years post‐HCT. Annual screening with biochemical markers is suggested. A 3.65 times higher incidence of diabetes mellitus (DM) compared with matched siblings has been reported in allogeneic‐HCT recipients [40]. At two years post‐HCT, up to one‐third of patients may develop DM [41], thereby suggesting a role for screening for DM at annual intervals. The development of DM itself may accelerate the rate of other known complications, including cataracts and chronic kidney disease.
Hypogonadism, fertility loss, pregnancy, and lactation issues
Hypogonadism to varying degrees is common after allogeneic‐HCT, and myeloablative regimens quite frequently lead to permanent sterility [42]. TBI or busulfan‐based therapies are major risk factors. Detailed fertility risk–benefit discussions pre‐HCT in patients of child‐bearing age are strongly suggested. Hormonal insufficiencies may manifest as loss of libido, erectile dysfunction, vaginal dryness, and dyspareunia. Hormonal assessment at six months post‐HCT and then annually with follicle‐stimulating hormone (FSH), luteinizing hormone (LH), and estrogen in females and FSH, LH, and testosterone in symptomatic males is recommended.
For those patients who wish to conceive and do not have any evidence of hypogonadism, a general approach is to recommend conception planning after two years of HCT since the majority of the primary disease relapses occur within that period. Since some allogeneic‐HCT patients are given maintenance chemotherapies, contraception may be utilized (if gonadal function normal) during that period of maintenance therapy to avoid pregnancy since the majority of the agents currently utilized for this purpose are teratogenic (e.g., hypomethylating agents). Similarly, those patients who are undergoing GVHD therapy may benefit from contraception, too, due to unknown teratogenic effects (e.g., CNI, sirolimus). Use of tyrosine kinase inhibitors for the treatment of cGVHD or post‐HCT maintenance therapy is a contraindication for pregnancy due to their known teratogenicity.
Besides the above‐mentioned potential late pregnancy/ fetal complications, caution must be exercised during lactation since most of the GVHD therapy drugs (CNI) are excreted in breast milk.
Musculoskeletal and bone complications
Osteopenia and avascular necrosis (AVN) of the hip or other joints are well described late bone effects of HCT which may occur as a result of corticosteroid therapy for GVHD [45]. AVN occurs frequently post‐HCT, and about 4–10% of the patients may be affected with at least one joint with AVN [46]. Vitamin D, plus calcium supplementation and annual dual‐energy X‐ray absorptiometry scans, for bone health are described in detail in Chapter 15.
Common late musculoskeletal effects include steroid‐induced myopathy, fasciitis/scleroderma, and polymyositis, and up to one‐third of patients may report musculoskeletal symptoms even after 10 years of HCT [47]. Sclerosis as a manifestation of cGVHD can affect the skin and subcutaneous tissues, including fasciae and joints. Prompt recognition of these complications by clinical examinations, serology, and neurologic studies and early intervention may prevent permanent disability.
Pulmonary complications
Infections (particularly aspergillosis, HHV‐6, CMV, respiratory syncytial virus, influenza, and parainfluenza viruses), BOS (bronchiolitis obliterans syndrome), COP (cryptogenic organizing pneumonia) and pulmonary thromboembolism are the main pulmonary late effects of allogeneic‐HCT. BOS occurs in 2–14% of allogeneic‐HCT recipients [48]. Smoking, TBI, chemotherapy (particularly busulfan), preexisting lung disease, and early HCT pulmonary complications are known risk factors. Surveillance strategies with history, examinations and pulmonary function tests at regular intervals post‐HCT may help to diagnose BOS in its early stage. This topic is further discussed elsewhere.
Neurologic complications
Late neurologic effects include neurocognitive defects, neuropathy, central nervous system (CNS) GVHD, and CNS infections. Neurocognitive impairment after allogeneic‐HCT is common, and up to 40% of the HCT survivors may exhibit cognitive deficits even five years post‐HCT [49, 78]. Neuropathy in HCT survivors is highly prevalent and frequently is a result of pre‐HCT chemotherapies. CNS GVHD is an understudied area, but evidence indicating specific inflammatory GVHD changes in the brain is accumulating [50, 51], and its diagnosis requires an aggressive approach with brain biopsy since cerebrospinal fluid (CSF) analysis and brain magnetic resonance images cannot differentiate CNS GVHD from other causes. CNS infections include HHV‐6 and CMV encephalitis (see “1. Acute and chronic infections”) besides the common microbial causes of meningitis. Myasthenia gravis and demyelinating diseases, including Guillain–Barré syndrome, are rare complications. Progressive multifocal encephalopathy should also be considered in the differential diagnosis of encephalopathies if rituximab was given pre‐HCT, or for treatment of cGVHD.
Psychological and social complications
The HCT survivors and their caregivers are at a significant
