complications
Late liver effects following allogeneic‐HCT include cGVHD, viral hepatitis, and drug‐induced hepatitis. Liver biopsies obtained from cGVHD patients have indicated chronic persistent hepatitis, lobular hepatitis, and reduction of small bile ducts with cholestasis, which resembles the pathologic manifestations of primary biliary cirrhosis. Untreated hepatic GVHD may lead to liver failure, which carries a very high mortality. Periodic evaluation with liver function tests (LFTs) may help in early diagnosis. Hepatitis B and C reactivations post‐HCT are rare, but a diagnostic workup must include the viral serology to exclude these conditions.
Some 7–64% of cancer patients utilize some form of complementary and alternative medicine (CAM) therapies, though a literature gap exists concerning this issue in the field of HCT. Many CAM therapies are known to be hepatotoxic and, in some cases, may lead to hepatic failure. Some of the more frequently reported hepatotoxic CAM therapies include the Chinese remedies [29], mistletoe [30], and kava [31]. Efforts should be made to obtain comprehensive CAM history and appropriate advice should be provided to those HCT patients who are using hepatotoxic CAM therapies to potentially avoid the possibly fatal late effect of hepatic failure.
Approximately one‐third of HCT survivors have evidence of iron overload [32] due to chronic transfusions during the pre‐ and peri‐HCT period that may lead to secondary hemochromatosis. It may be reasonable to evaluate serum ferritin levels at 6–12 months post‐HCT; and for patients in whom the evidence of iron overload is found, the general principles of secondary hemochromatosis should be applied for organ‐specific screening for complications (e.g., surveillance with ultrasound for liver cancers). Patients with evidence of significant iron overload can be considered for therapeutic phlebotomy if there is an adequate recovery of erythropoiesis or possibly for iron chelation therapy.
Gastrointestinal complications
Apart from the oral cavity complications (see Oral cavity complications” earlier), gastrointestinal (GI) involvement with cGVHD is not uncommon. Common manifestations include involvement of the esophagus, resulting in progressive dysphagia, painful ulcers, and gradual weight loss and esophageal webs. Since the incidence of secondary cancers is also increased in allogeneic‐HCT patients, endoscopies should be performed in patients with symptoms of dysphagia. Abdominal pain/cramping, nausea/ vomiting, weight loss, diarrhea, and early satiety are also common in GI GVHD [33].
Apart from GI GVHD, late GI effects include GI cancers, medication adverse effects, which include steroid‐induced gastritis/esophagitis, mycophenolate‐induced colitis, and lastly infections particularly due to CMV colitis. Prompt recognition and treatment of these conditions is warranted to avoid complications.
Genital complications
In females, the most frequent late effect manifesting as a genital complaint is vaginal–vulvar GVHD. It typically occurs around the 10th month post‐HCT and presents with vaginal pain, discomfort, and vaginal scarring [34]. As this late effect can be successfully treated with topical cyclosporine/steroids/estrogen therapies in the early stages, vaginal examinations at regular intervals (see Chapters 18 and 23) should be performed for early detection. Other late effects include cervical cancers, vaginal candidiasis, and herpes simplex infections.
In 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.