Introduction:Hematologicstem cell transplant (HCT) is potentially a curative treatment option forvariety of hematologic diseases.
Advances in the field of HCT over the pastdecade due to safer conditioning regimens, better post-transplant supportivecare, and alternative graft sources has markedly increased the number oftransplants performed leading to an increase in long-term survivors (Figure 1).This success has also brought the recognition of long-term health impact of HCTsuchas cardiopulmonary compromise, musculoskeletal disorders, endocrinopathies, andsubsequent malignancies. Thesecomplications have the potential for substantial morbidity and mortality and negativelyimpact quality of life among HCT survivors. Continued lifelong surveillance forprevention, early detection and timely treatment of late complications is criticalto optimize long-term outcomes. This review will describe the burden ofmorbidity experienced by HCT survivors and provide an overview of currentfollow-up recommendations.
Long-term survival after HCT: Theprospect for long-term survival is excellent for 2-year survivors of allogeneicHCT. Based on Center for International Blood and Marrow Registery (CIBMTR)retrospective study of 10,632 allogeneic HCT recipients, 85% of those who werealive and disease free 2 years after allogeneic HCT are expected to become along-term survivor. However, life expectancyof HCT survivors continues to lag behind that of age- and gender-matchedgeneral population for at least 15 to 20 years after HCT. Disease relapse isthe most common cause of late death among patients with malignantdisorders. In most cases recurrentmalignancy occurs within the first 2 years after the transplant, with fewoccurring more than 5 years after the transplant. Therefore,intense surveillance for recurrent malignancy after 5 years can be reduced.
Followingdisease relapse, other causes of late deaths are chronic graft versus host disease (GVHD), organ toxicity, lateinfections and secondary cancers (Figure 2).Organtoxicity: The following highlights the most common organtoxicity seen after HCT and recommendations for screening and prevention basedon Recommended Screeningand Preventive PracticesCardiovascularcomplications-HCT survivors havean increased risk for cardiovascularcomplications such as coronary artery disease, peripheral arterial disease andcardiomyopathy. There is a 2-fold increase in risk of cardiovascular deathamong HCT survivors compared with the general population. Early onsetcardiovascular events are primarily due to accelerated atherosclerosis due toradiation (pre-transplant or total body irradiation as a part of transplantconditioning regimen). HCTsurvivors also have a high prevalence of metabolic syndrome which represents acluster of risk conditions associated with premature coronary artery disease. Education and counseling on “heart Healthy” lifestyleincluding a regular exercise, healthy dietary habits and screening fordyslipidemia, diabetes and hypertension should be recommended to all HCTsurvivors. Routine clinical assessment of cardiovascular risk factors isstrongly recommended at 12 months post-transplant and annually afterwards.
In asymptomaticadults without any cardiac risk factors, cardiac imaging tests are notrecommended. More frequent assessments and if clinically appropriate, further cardiacevaluations may be indicated in patients at high-risk for cardiac complicationsincluding patients who had mediastinal radiation, patients with amyloidosis,and those with pre-existing cardiac and vascular complications.EndocrineComplications–Thyroid dysfunction Thyroid dysfunction is among the most commonlong-term endocrine complications post autologous and allogeneic HCT.
Total body radiation (TBI), youngerage at transplant and presence of GVHD are the most recognized risk factors forthyroid dysfunction after HCT. Based on international blood and marrowtransplant guidelines, thyroid function assessment is recommended yearly after HCTindefinitelyor in presence of relevant symptoms.Gonadaldysfunction isvery common in HCT, recipients affecting as high as 92% for males and 99% forfemales. Age at transplantation, gender, pre-transplant therapy and intensityof conditioning regimen (especially high dose irradiation and busulfan) influencethe degree of gonadal dysfunction. Women who were post-pubertal at thetime of transplantation should have clinical and endocrinologic gonadalassessment 1 year after HCT. Subsequent assessment should be guided bymenopausal status. Gonadalfunction in men (FSH, LH, and testosterone) is warranted by symptoms. Skeletalcomplications-Lossof bone density is a well-known complication of HCT with reported incidencerates as high as 25% for osteoporosis and 50% for osteopenia in some studies.
Olderage, female gender, low body mass index, physical inactivity and prolongedsystemic corticosteroids exposure (? 5 mg prednisone equivalent daily for >3months) are well-recognized risk factors. Dual photon densitometry (DEXA scan)for adult women, all allogeneic HCT recipients, and patients at high risk ofbone loss after HCT is recommended one year post HCT. Subsequent testing isdetermined by the findings of first DEXA Scan or to assess therapy response.Education and counseling of HCT survivors about physical activity, vitamin Dand calcium supplementation is highly recommended to prevent bone density loss.
Avascularnecrosis (ANV) of the bone is another debilitating skeletal compilation postallogeneic HCT with a cumulative incidence of 3% to 10% at 5 years after HCT.In addition to risk factors for osteoporosis , TBI as a part of conditioningregimen has been associated with AVN. Joint pain and discomfort is the firstmanifestation of AVN. Most commonly affected joints are hips (more than 80% ofcases), knees and wrists. Standard imaging (X-ray) may not detect theabnormality until late stages of the disease. Thus, MRI imaging in patientswith persistent joint pain with higher risk of AVN for early detection andprompt referral to an orthopedic specialist is recommended. Ocular complications- Cataract and sicca syndrome are amongst the most commonocular complications after HCT.TBI as sequelae from the preparative regimen andprolonged use of corticosteroids after.
The median time to develop cataractsafter transplant ranges from 2 to 5 years. An annual eye exam with slit lampexamination is recommended for all patients who have had an allogeneic HCT andfor those who are at risk of cataracts. OralComplications- Theoral cavity is one of the sites most commonly affected by chronic GVHD afterallogeneic HCT. Impact of chronic GVHD on salivary glands lead to qualitativeand quantitative salivary changes (dry mouth) leading to development of dentalcaries. Patients with a history of oral chronic GVHD are at risk of developmentof intra-oral malignancy (especially, squamous cell oral cancer). Routineclinical oral assessment and dental health examinations are strongly recommended6 months and 1 year post-transplantand annually afterwards. More frequentoral examination (every 6 months)is required in patients with chronic GVHD,oral mucosal lichenoid lesions, and/or a history ofFanconi’s anemia.
Patients should be encouraged to carry out effective oral hygiene,avoid smoking and chewing tobacco, and perform oral self-inspection.ChronicGVHD, a potentially life-threatening post-transplant complication, occurs inapproximately 40% to 70% of recipients of allogeneic HCT. It is an immune response of the donor T cellsagainst recipient tissues. Chronic GVHD is not only a major cause ofnon-relapse mortality, it can lead to significant morbidity and decline inhealth-related quality of life.
Thus, ongoing surveillance and earlyrecognition of signs and symptoms of chronic GVHD is critical tooptimize long-term outcomes (Table 1). When signs of chronic GVHD appearscollaboration with the transplant center to confirm diagnosis and management isnecessary. Post-HCTvaccination: Levelsof antibodies to diseases that can be prevented by vaccination decrease significantly within the first few yearsafter HCT. Therefore,patients should be routinely revaccinated after transplant until they regainimmune competence. Table 2 outlines the vaccination schedulefor autologous and allogeneic HCT recipients based on international consensusguidelines.
Live vaccinations including (Measles-mumps-rubella)MMR and varicella-zoster vaccination should not be administered to individualswith active GVHD,on immunosuppressanttherapy and patients less than 2 yearspost HCT.It is strongly recommended thatthe patient’s family members and close contacts be current on vaccinations tohelp protect the patient from exposure to infectious diseases.Patient’s familymembers or close contacts can safely receive inactivated vaccines according tothe recommended Centers for Disease Control and Prevention (CDC) schedule. Secondarymalignancies including post-transplant lymphoproliferative disorder (PTLD),myelodysplasia (MDS), acute myeloid leukemia (AML), and solid tumors arewell established complicationsin long-term HCT survivors. Risk factorsassociated with the development of secondary cancers include geneticpredispositions of patient to develop cancer, older age at the time oftransplant, use of TBI, chronic GVHD, and prolonged immunosuppressive therapy. MDS,AML and PTLD develop relatively early in the post-transplant period. Solidtumors have a longer latency time. Survivors of HCT have a 2 to3-fold increased risk of developing subsequent solid cancers compared with the generalpopulation.
Large retrospectiveseries have estimated the cumulative incidence rates of secondary solid tumorsat 1 to 2 percent at 10 years and 3 to 5 percent at 20 years after allogeneicHCT. Cancers that occur at increased frequency include skin cancers (squamouscell, basal cell, and malignant melanoma), cancers of the buccal cavity, liver,central nervous system, thyroid, bone, and connective tissue. Therefore, itis important to notify HCT survivors regarding an increased risk ofdeveloping a malignancy following HCT and encourage in healthy behaviors(healthy diet, exercise, smoke cessation) and encourage report of anyconcerning symptoms. It is also important to encourage patients to reduce sunexposure through use of high SPF sunscreens or skin coverage. In addition to aroutine physical examination, annual complete skin examination and dentalevaluation to monitor for the development of skin and oral cancers isrecommended. More frequent oralexamination is required in patients with chronic GVHD, oral mucosal lichenoidlesions, and/or a history of Fanconi’s anemia.
Female HCT survivors screening for breast cancer should start at age 40years. For patients who have received total body or chest irradiation, breastcancer screening begins eight years after radiation or at age 25 years,whichever occurs later. Routineage-appropriate cancer surveillance for other secondary malignancies shouldfollow the recommendations outlined under the General Health and PreventiveScreening section.