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Bone Marrow Transplantation (2016) 51, 1025–1031 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/16 www.nature.com/bmt

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What do we need to know about allogeneic hematopoietic stem cell transplant survivors? CA Clark1, M Savani2, M Mohty3,4,5 and BN Savani1 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for over 70 benign and malignant hematologic and immunological processes. Over the past several decades, significant technological and post-transplant supportive advances have been made, resulting in a decrease in early transplant mortality and continued growth in the population of alloHSCT survivors. With the expansion in the number of long-term survivors, as well as of those considering a transplant, the focus of transplant medicine has been shifted significantly to include a more prominent role for the care of the ‘long-term’ survivor. These patients have survived the acute critical phase of transplantation and have potentially achieved remission from their primary disease, yet allo-HSCT patients do not return to pre-transplant health status. For survivors 42 years removed, the time of transplant all-cause mortality is four- to nine-fold higher than age-matched peers within the general population. These patients represent a distinct, high-risk population that must be monitored for long-term transplant complications, including chronic GvHD (cGvHD), multi-organ dysfunctions and secondary malignancies. This article will review in a non-exhaustive manner, the approach to long-term care of an allo-HSCT recipient. Bone Marrow Transplantation (2016) 51, 1025–1031; doi:10.1038/bmt.2016.95; published online 11 April 2016 ‘SURVIVORSHIP’ INTRODUCTION Survivorship can be a nebulous concept to define. For some it may simply mean the number of patients alive at 2 years after allo-HSCT. But for an increasing number of patients and medical providers, survivorship has come to encompass not merely living past an arbitrary milestone, but the expectation of the return to physical well-being and the continuation of the pursuit of a meaningful life. This excerpt is devoted to this idea of survivorship, recognizing that each transplant recipient will have different expectations, and face different challenges and triumphs.1 HOW DID WE GET HERE? Nearly 50 years have passed since the first successful series of allo-HSCTs were performed in the late 1960s. Growth in the number of transplants performed occurred slowly at first, but the last two decades has seen a rapid expansion in the number of allo-HSCTs performed around the globe.2 In fact, the European Society of Blood and Marrow Transplantation reported in its latest annual survey that the number of allo-HSCT had doubled in Europe over the previous 10 years.3 In addition, the Worldwide Network for Blood and Marrow Transplantation now estimates that 450 000 patients are transplanted worldwide annually; significant proportions of these transplants are allogeneic.3–5 It is now estimated that by 2020 there may be up to half a million long-term all-type HSCT survivors across the globe.2,5 This growth has largely been attributable to the increasing use of unrelated donors and reduced intensity transplant conditioning regimens. Concomitantly, growth in transplant eligible patients has been accompanied by advances in transplant strategies, donor selection and supportive care, and by an expansion in the potential donor

pool through the increasing availability of affordable HLA typing methods. WHERE SHOULD THE TRANSPLANT SURVIVOR BE FOLLOWED? Numerous models have been proposed to accommodate follow-up care for the rising number of long-term allo-HSCT survivors. A number of institutions have adopted HSCT-specific survivor clinics, which provide at minimum an annual multidisciplinary follow-up. As these clinics face an everincreasing workload with numerous transplant patient survivors, it is imperative to consider models that serve best to address the issue of the demands and limited resources to provide the best care for these patients. Other institutions have adopted models that rely on survivor care plans and the utilization of primary care-driven disease and transplant complication surveillance. This survivor care plan model has been advocated by the Institute of Medicine 2005 Report entitled From Cancer Patient to Cancer Survivor: Lost in Transition.5 No particular model is optimal for every patient, and considerations must be made for: ● ● ● ● ● ●

Personnel resources Material resources Transplant program size Patient demographics Geographical area covered by transplant center Transplant expertize level of primary care providers within the region

Often, the exact strategy to approach survivorship care is individualized to the particular needs of the patient, both from a disease complication burden and logistical standpoint. Whatever

1 Department of Internal Medicine, Hematology and Stem Cell Transplant Section, Vanderbilt University Medical Center, Nashville, TN, USA; 2The University of Tennessee Heath Science Center, College of Medicine, Memphis, TN, USA; 3Department of Haematology, Saint Antoine Hospital, Paris, France; 4INSERMUMR 938, Paris, France and 5Université Pierre et Marie Curie, Paris, France. Correspondence: Professor BN Savani, Hematology and Stem Cell Transplant Section, Vanderbilt University Medical Center, 1301 Medical Center Dr, 2665 TVC, Nashville, 37212 TN, USA. E-mail: [email protected] Received 22 November 2015; revised 2 March 2016; accepted 3 March 2016; published online 11 April 2016

Allogeneic hematopoietic stem cell transplant survivors CA Clark et al

1026 the strategy, care is optimized when the survivor has lifelong contact with a core transplant provider group, and when expectations and responsibilities of care are clearly coordinated with a multidisciplinary support team, which is inclusive of a wide array of consultants experienced in transplant-related complications. LATE EFFECTS OF HSCT Most late effects usually arise secondary to an interaction of factors including, but not limited to cGvHD, prolonged immunosuppression, poor health at baseline, as well as effects of chemotherapy/radiation preparative regimens for allo-HSCT. Owing to these multifactorial interactions, and the lack of a strict and systematic timeline for progression of complications, it has been difficult to formulate a definitive guideline for important post-transplant landmarks. Late effects have traditionally been defined as complications arising at least 6 months after transplantation; very late effects have been classified as complications arising at least 5 years after transplant. However, these distinctions have largely fallen out of favor within the transplant community, recognizing for instance that secondary malignancies, although more commonly occurring within the very late period, may certainly also occur within the first 5 years of transplant. A general strategy outline for prevention, surveillance and early treatment of long-term complications by organ system will be provided in the following sections. CHRONIC GVHD Originally described as an allograft host inflammatory process occurring at least 100 days post transplantation, cGvHD is now characterized as a distinct systemic process with many auto-immune-like qualities whose presentation may occur at any point after transplantation. The National Institutes of Health has established diagnostic criteria, which if present are sufficient to diagnose cGvHD, as well as distinctive features, which if present suggest cGvHD, but require the definitive diagnosis to be confirmed by biopsy, laboratory testing or radiological imaging.6 In one large multivariate analysis, cGvHD was estimated to occur in 37% allo-HSCT recipients at 1 year from time of transplant, and has been increasing over the past decade.7 Although it can affect essentially any organ system, disease manifestation has a predilection for oral and ocular mucosa, skin, lung, liver, gastrointestinal and genitourinary tract epithelium. Whether it is implicated directly or indirectly, cGvHD is the number one cause of mortality in long-term allo-HSCT recipients. What are the major risk factors for cGvHD? ● Documented prior acute GvHD ● Higher degree of HLA mismatching ● History of allo-immunization before transplant ● Gender disparity between donor and recipient ● Older age at transplantation ● Use of PBSC transplantation. What are the implications for the development of cGvHD? ● Necessitating the extended use of immunosuppressive therapy ● Higher risk of infection from encapsulated bacterial organisms, Pneumocystis jiorvecii, CMV and fungal organisms ● Delayed immune reconstitution ● Decreased quality of life measures ● Endocrine dysfunction ● Obstructive lung disease Bone Marrow Transplantation (2016) 1025 – 1031

● ●

Microvascular disorders Increased risk of secondary malignancies

Clinical point cGvHD is typically tracked in long-term allo-HSCT clinic using an organ system scoring system to monitor for disease progression and for response to therapy. Scoring assessments may be performed every 3–4 months initially, and typically spaced out to longer intervals as the time from transplant advances.6 SECONDARY MALIGNANCIES Secondary malignancies are an increasingly recognized complication of HSCT recipients. Overall incidence of malignancy has been estimated to be 3–4% at 10 years and 10–12% at 15 years. And, mortality from secondary neoplasms is estimated to be the cause of 5–10% of deaths post HSCT.2,8–11 Most secondary malignancies after allo-HSCT can generally be classified into one of the three categories: post-transplant lymphoproliferative disorders (PTLDs), myelogenous malignancies and solid tumors. General risk factors for the development of secondary malignancies include younger age at transplant, therapeutic radiation exposure before transplant, increased number of chemotherapy cycles, cGvHD and prolonged immunosuppressive therapy. PTLD ● Most common secondary malignancy in first year after transplant. ● Unlike solid organ recipients, usually originates from donor tissue. ● Relationship between EBV and chronic immunosuppression has been well characterized. ● Younger age at transplant and EBV seronegative patients with seropositive donors are at highest risk. ● Other highly associated risks are the use of T-cell depleted graft, HLA mismatch, presence of GvHD and history of splenectomy. Myelogenous malignancies ● Tend to present later than PTLDs. ● Median time from transplant is 12–40 months. ● Typically arising from donor tissue. ● Exact pathogenesis has not been entirely elucidated, but is thought to be related to antigenic stimulation of donor cells from host tissue. Solid tumors ● Much longer latency period, median time at onset up to 3–7 years post transplant. ● Incidence post transplant does not plateau, unlike PTLD or myelogenous malignancies that decline before the end of first decade post transplant. ● Major risk factors include chemo/radiation exposure and chronic inflammation. ● Relative risk is estimated to be greater than two- to threefold compared with age-matched peers, and beyond 10 years may be even higher. ● Some of the more common secondary solid malignancies include buccal cavity squamous cell, melanoma, thyroid, brain, liver and connective tissue neoplasms, including sarcomas. Clinical point Patients should be encouraged to perform regular selfexaminations of their skin, breasts and testicles. Annual mammograms should begin at age 40 years or at 10 years post transplant © 2016 Macmillan Publishers Limited, part of Springer Nature.

Allogeneic hematopoietic stem cell transplant survivors CA Clark et al

1027 if younger than 40 years. The Human Papillomavirus vaccination should be offered to both sexes at 1 year post transplant, or once off immunosuppressive therapy if older than 12 years of age. In patients with cGvHD, clinical and dental evaluation with an emphasis on oral and pharyngeal cancer is also recommended. Moreover, HSCT patients follow general population guidelines for screening colorectal cancer; colonoscopy every 10 years, starting at age 50 years, is recommended. Furthermore, among the recipients of TBI or chest irradiation, screening for breast cancer is recommended at an earlier age (25 or 8 years after radiation, whichever occurs later), but no later than age 40 years.9,12 INFECTIOUS/IMMUNIZATION The time frame for infectious complications post allo-HSCT can in general be broken down by periods. The pre-engraftment period is characterized by neutropenia secondary to conditioning regimens. In the early post allo-engraftment period extending to 3 months after transplant risk is largely secondary to a naive immune system and the possible presence of GvHD. In the late engraftment period, designated as 3 months post transplant, risk is governed by cGvHD and the necessity for immunosuppression therapy.2,13 Bacterial ● The presence of cGvHD can often lead to functional asplenia, increasing the susceptibility to encapsulated organisms including: Streptococcus pneumoniae, Haemophilus influenza and Neisseria meningitidis. ● Nocardia can be seen in long-term allo-HSCT recipients and may clinically resemble aspergillosis. ● Clostridium difficile is a very common nosocomial infections. Viral ●









Owing to its high association with late-term mortality, CMV reactivation or primary infection must be monitored closely. Prophylactic doses of acyclovir or valacyclovir have been shown to be well tolerated and effective, and may reduce the need for definitive treatment by 50%.14 EBV reactivation or primary infection has a close association with PTLDs. Antiviral prophylaxis has not affected the incidence of PTLDs, but close monitoring of EBV status and viral load is recommended. Antiviral prophylaxis is recommended in HSV seropositive patients and should continue for as long as the patient is receiving immunosuppressive therapy. Risk of varicella zoster reactivation is highest in the first year, and declines significantly 2 years after transplant. Prophylaxis is recommended for at least 1 year post transplant or as long as the patient is on immunosuppression. JC/BK, HIV, hepatitis B and C infections and reactivations are rare late effects and do need long-term surveillance in patients on prolonged immunosuppressive therapy, but a high index of suspicion is required in the right clinical setting.



WHEN SHOULD PATIENTS BE REVACCINATED? Allo-HSCT recipients should be revaccinated because immunization to common pathogens is lost after transplantation. The decreased functional capacity of T and B cells after transplant dictates that immunization in general should be performed at 6–12 months. Live vaccines such as measles, mumps and rubella, and varicella should be given at 24 months in the absence of cGvHD or ongoing immunosuppression. Our institutional vaccination recommendations are summarized in Table 1 (adapted from published society guidelines).2,12,16 CUTANEOUS COMPLICATIONS Cutaneous involvement is the most common presentation of cGvHD and is estimated to occur to some extent in approximately 75% of allo-transplant recipients. Cutaneous GvHD has a remarkable variety of dermal manifestations but can be generally categorized as sclerotic vs non-sclerotic type.17 Patterns of clinical manifestations summarized in Table 2 (adapted from Olivieri et al).17 In addition to lower quality of life metrics, patients with cutaneous GvHD are at increased risk of infectious complications associated with mucosal barrier breakdown and long-term use of immunosuppressant therapy. Furthermore, cutaneous GvHD can herald visceral involvement and confers higher mortality rates compared with age-matched peers. Clinical point Assessment of clinical features, severity and extent of cutaneous manifestations is vital to provide disease prognosis, as well as to monitor for treatment response. Therefore, early diagnosis and frequent monitoring in designated long-term follow-up clinics with referral capabilities to dermatological subspecialists is critical. GASTROINTESTINAL Chronic gastrointestinal complaints in the allo-HSCT recipient population are largely attributable to GvHD and high infectious risk-associated immunosuppressive agents.2,18 ●



Fungal Major risk factors include neutropenia, cGvHD and CMV infection. ●



Candida vulnerability is attributable to mucosal injury from cGvHD, as well as functional neutropenia. Prophylaxis should be provided while undergoing active immunosuppression therapy (typically fluconazole). Aspergillus vulnerability most commonly occurs with profound T-cell deficiency. Second generation azoles such as itraconazole and voriconazole have been shown superior to fluconazole for prophylaxis.15 Prophylaxis should be considered in high-risk patients.

© 2016 Macmillan Publishers Limited, part of Springer Nature.

Pneumocystis jiorvecii is a common interstitial pneumonia pathogen in susceptible patients without prophylaxis. Trimethoprim–sulfamethoxazole is recommended while on immunosuppressive therapy. If the patient is intolerant dapsone, atovaquone or inhaled pentamidine may be considered.





Esophageal complications include late acute GvHD, cGvHD, infectious esophagitis and reflux pathology. Symptoms of dysphagia, odynophagia may require work-up with swallow studies or endoscopy, especially if associated with anorexia, malnutrition and weight loss. Pancreatic complications include insufficiency, as well as acute and chronic pancreatitis. These complications are thought secondary to immunosuppressive agents, biliary stones and sludge secondary to conditioning regimens, as well as ductal obstruction directly attributable to GvHD. Chronic GI GvHD can present as abdominal pain, diarrhea, bloating and vomiting. Diagnosis should be made with endoscopy and correspondent pathology in the right clinical setting. Additional causes of abdominal pain and diarrhea include infectious etiologies (especially among those currently being treated for cGvHD) including: C. difficile, HSV, CMV, enteric VZV and parasitic infections such as giardia. Bone Marrow Transplantation (2016) 1025 – 1031

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1028 Table 1.

Institutional vaccinations recommendation for HCT recipients

Vaccine

Recommendation after HCT

Time post HCT to initiate vaccine (months)

Number of doses

PCV

Yes

3–6a

3–4a

Tetanus, diphtheria and acellular pertussisb

Yes Tetanus–diphtheria

6–12

3c

Haemophilus influenza conjugate Meningococcal conjugate Inactivated polio Recombinant hepatitis B Inactivated influenza Measles, mumps and rubellaf

Yes

6–12 6–12 6–12 6–12 4–6 24

3 1 3 3 1–2e 1–2g

Yearly

Improved by donor vaccination Yes, may be considered when recipient is at high risk for GvHD Tetanus: likely Diphtheria: likely Pertussis: Unknown Yes Unknown Unknown Likelyd Unknown Unknown

Abbreviations: HCT = hematopoietic stem cell transplant; PCV = pneumococcal conjugate. aIf immunization is started early, consider evaluating for Ab levels and if they are low, revaccinate. Following the primary series of three PCV doses, a dose of the 23-valent polysaccharide pneumococcal vaccine (PPSV23) to broaden the immune response. Administer PCV (for example, prevnar) and PPSV23 (for example, pneumovax) at 8 week intervals; booster dosing (with both PCV and PPSV23 every 2–3 years, also in patients with negative annual pneumococcoal titers). bTetanus, Diphtheria and Pertussis vaccination (DTaP) is preferred, however, if only Tdap is available (for example, because DTaP is not licensed for adults), administer Tdap. Acellular pertussis vaccine is preferred, but the whole-cell pertussis vaccine should be used if it is the only pertussis vaccine available. cSee text for consideration of an additional dose(s) of Tdap for older children and adults. dSignificant improvement of recipient response to hepatitis B vaccine post transplant can be expected only if the donor receives more than one hepatitis vaccine dose before donation. eFor children o9 years of age, two doses are recommended yearly between transplant and 9 years of age. f Measles, mumps and rubella vaccines are usually given together as a combination vaccine. In females with pregnancy potential, vaccination with rubella vaccine either as a single or a combination vaccine is indicated. gA uniform specific interval between doses cannot be recommended, as various intervals have been used in studies.

International Normalized Ratio (INR), hypoalbuminemia and thrombocytopenia

Table 2.

Pattern of cutaneous manifestations in long-term survivors after transplantation Site

Diagnostic

Distinctive

Other common findings

Skin

Poikiloderma Lichen planus like Sclerotic features Morphea like Lichen sclerosis like

Depigmentation Papulosquamous lesions

Erythema Maculopapular rash Pruritus

Nails

Scalp and hair

Dystrophy Longitudinal ridging Onycholysis Pteryguium unguis Symmetric nail loss New onset scarring or Thinning scalp non-scarring scalp hair alopecia Premature gray Loss of body hair Scaling

LIVER Hepatic abnormalities in the long-term post-transplant period can reflect hepatic GvHD, iron overload, viral hepatitis, non alcoholic fatty liver disease or drug-induced liver injury. In addition, patients are at risk for the same common hepatic processes as the general public.2,18 Chronic liver GvHD may present with various hepatic patterns. These include: ● ● ● ●

Chronic asymptomatic elevation of aspartate transaminase/ alanine transaminase (AST/ALT) Progressive cholestatic pattern Acute hepatocellular injury If inflammation or cirrhosis is advanced, synthetic function may be impaired and may be reflected as elevated

Bone Marrow Transplantation (2016) 1025 – 1031

Iron overload can become a problem in allo-HSCT recipients, particularly in those requiring multiple blood transfusions in the peri-transplant period. Iron studies will likely reveal a non-specific elevation of ferritin or iron saturation; however, a hepatic biopsy or magnetic resonance imaging liver (FerriScan, Resonance Health Limited & Resonance Health Analysis Services Pty Limited, Claremont, WA, Australia) may be required for definitive diagnosis. Non alcoholic fatty liver disease can be seen in transplant survivors, particularly those with acquired dyslipidemias, those with poor dietary habits and sedentary lifestyles that are often adopted owing to poor quality of life and post-transplant complications. Clinical point We suggest checking Liver Function at regular intervals, 3–6 months after transplant, and on an annual basis thereafter in high-risk patients. Abnormal hepatic values should prompt further work-up, possible hepatology consult, and if necessary consideration for imaging (magnetic resonance imaging-FerriScan) or a liver biopsy. PULMONARY Chronic obstructive pulmonary diseases occur in up to 20% of long-term survivors; cGvHD, TBI, hypo-gammaglobulinemia and various infectious exposures are thought to contribute.19,20 Of particular concern is the development of bronchiolitis obliterans syndrome, a severe form of large and small airway obstruction characterized by lymphocytic infiltration, likely secondary to donor alloreactivity. Special consideration should be employed in patients with known risk factors for bronchiolitis obliterans including: ● ● ● ●

Busulfan conditioning regimens Prior respiratory infections in the peri-transplant period Peripheral stem cell transplantation Evidence of extra-pulmonary cGvHD © 2016 Macmillan Publishers Limited, part of Springer Nature.

Allogeneic hematopoietic stem cell transplant survivors CA Clark et al

1029 Initial investigation of bronchiolitis obliterans should ideally be done in comparison to pre-transplant pulmonary function tests and should be inclusive of an extensive work-up. Clinical point Current recommendations from the American Society of Blood and Marrow Transplantation are that screening pre-transplant pulmonary function tests should be performed at baseline, 6 months, 1 year and then annually if clinically indicated in patients with history of abnormal pre-transplant pulmonary function tests and/ or ongoing cGvHD. It is recommended that screening should occur more frequently in high-risk patients with clinical manifestations of cGvHD. ORAL CAVITY Allo-HSCT recipients are at risk of a wide variety of oral complications. A large portion of oral pathology may be attributable at least in part to cGvHD. Mucosal atrophy, lichenoid lesions and ulcerations can cause significant discomfort, and limit the patient’s ability to tolerate a balanced diet. Chronic xerostomia and salivary gland dysfunction put patients at risk for dental caries and periodontal disease. Clinical point Routine oral examination should be included in each return clinic visit, and regular dental appointments should be encouraged. In addition, a large portion of secondary solid tumors post transplantation present as oral lesions; any new, non-healing ulcers or raised, indurated lesions should be considered for biopsy. OPHTHALMOLOGICAL The two most common late ocular complications following alloHSCT are cataract formation and dry eye syndrome. Both processes can result in significant loss of visual acuity, and if untreated may cause a significant decrease in quality of life. Cataract formation is closely associated with TBI preparative regimen. Formation begins to appear usually within 3–5 years, and the incidence following fractionated TBI appears to be between 40 and 70%.2,10,21,22 Dry eye syndrome occurs in 40–75% of allo-HSCT recipients, and may be the heralding symptom of ocular GvHD.23 Secondary complications include conjunctival keratitis, corneal keratinization, ulceration and perforation of the cornea. These and other epithelial defects may be prevented by early detection and treatment. Clinical point Evaluation of visual acuity should occur at 6 months, 1 year and annual thereafter. Concern for dry eye syndrome or ocular GvHD warrants an ophthalmology consult. ENDOCRINE The post-transplant incidence of diabetes mellitus has been observed to be as high as 30% within the first 2 years.2,24,25 Although some cases resolve, the prevalence of diabetes remains elevated in comparison with the non-transplanted population. Risk factors include age at transplant, obesity, preparative TBI, documented cGvHD and its associated immunosuppression. The pathophysiology of post-transplant diabetes mellitus shares features of type 1 and type 2 diabetes mellitus. cGvHD, relative T-regulatory cell deficiency and an alteration of the anti-inflammatory milieu after transplantation are thought to decrease beta islet cell function. In addition, the use of corticosteroids has been well known induce insulin resistance. © 2016 Macmillan Publishers Limited, part of Springer Nature.

Identification of patients at risk of diabetes is essential to advise patients with modifiable risk factors such as obesity, hyperlipidemia, hypertension and a sedentary lifestyle. Although no specific guidelines for screening diabetes have been created for the post allo-HSCT patient population, it is generally recommended that screening occur frequently in the first year after transplant, and at least annually in the long-term population. Hypothyroidism has an estimated incidence of 5–25% in the first year, following allo-HSCT transplant and the prevalence of disease may increase as the time from transplant increases.26 Risk factors include TBI regimens, GvHD, and CMV infection or reactivation.25 Although less common than hypothyroidism, hyperthyroidism can also occur with an estimated occurrence of 15% at 1 year post transplant. Several mechanisms have been proposed, including allograft autoimmunity and an increased incidence of infective thyroiditis in the first years after transplant. Clinical point We support obtaining thyroid stimulating hormone and free T4 tabs at the time of transplant, in the first 3–6 months following transplant and on a yearly basis thereafter. Dyslipidemia after transplant is a common problem, and one large study has reported an estimated incidence of hypercholesterolemia to be ~ 73% within the first 2 years following transplant.27 Risk factors for hypercholesterolemia are cGvHD, as well as obesity before transplantation. Immunosuppressant regimens including glucocorticoids, tacrolimus and cyclosporine have been well known to worsen dyslipidemia. The American Society for Blood and Marrow Transplantation recommends that screening for dyslipidemia should begin at least at 1 year after transplantation (early screening is preferred) and annually thereafter. CARDIOVASCULAR Mortality attributed to cardiovascular events appears to be at least two times higher in allo-HSCT recipients compared with age-matched peers, and is likely underestimated because of a paucity of very long-term survivor data.28,29 The most important risk factors for the development of post allo-HSCT cardiomyopathy are the lifetime cumulative dose of anthracyclines, TBI conditioning regimens, preceding co-morbidities, as well as traditional cardiovascular risk factors such as: age, gender, smoking, hypertension, family history and hyperlipidemia. Higher-risk patients, especially those with traditional cardiac risk factors, should undergo regular monitoring, typically with echocardiography, stress testing and electrocardiography to detect early cardiac functional impairment. In 2008 the Late Effects Working Party of European Bone Marrow Transplantation published a retrospective multicenter analysis reporting a six-fold-increased risk of arterial event (cerebrovascular, coronary or peripheral vascular) for patients older than 30 years at the time of transplant.30 This and additional data suggests that allo-HSCT patients are at increased risk for the development of cardiovascular disease, and experience cardiovascular events at a premature age compared with the general population. Endothelial injury secondary to inflammation associated with chemotherapeutic regimens, TBI and cGvHD has been implicated as the nidus for early atherosclerotic changes. Furthermore, atherosclerosis within this population is likely augmented by a higher incidence of: ● ● ● ● ● ●

Dyslipidemia Hypothyroidism Hypogonadism Diabetes mellitus Hypertension Renal disease Bone Marrow Transplantation (2016) 1025 – 1031

Allogeneic hematopoietic stem cell transplant survivors CA Clark et al

1030 Clinical point It is imperative to routinely screen for modifiable cardiovascular risk factors. Blood pressure measurement should occur at regular intervals, lifestyle modification counseling should be offered for obese and sedentary populations, and lipid and glucose profiles should be obtained at baseline at 1 year post transplant, and annually thereafter for high-risk patients. PSYCHOSOCIAL The transition from transplant patient to transplant survivor can prove arduous. Survivors may continue to experience distress over potential disease reoccurrence, treatment-related financial constraints, caregiver- patient stressors, significant morbidity and physical limitations associated with cGvHD, and concern over the development of secondary malignancies. The transition back to the workplace, school and regular family life may prove to be more difficult than expected because of significant physical and psychological detractors. In many instances a patient’s career goals, spirituality and life outlook may have been altered by their transplant experience.31,32 Rates of depression among the general cancer population range from 10–25%. Among the allo-HSCT transplant population the prevalence may be even greater; some studies have suggested rates of depression to be as high as 25–35% within the first year after transplant. Furthermore, several studies have suggested a link between depressive symptoms and decreased survival among allo-HSCT recipients.31,33 This may reflect higher levels of overall distress attributable to more intense induction regimens, higher financial and time constraints, and more significant disease complications when compared with other oncologic patient groups. In addition, the incidence of post traumatic stress disorder (PTSD) may be as high as 5% in transplant survivors. Moreover, one European study has indicated that the suicide death rate per 100 000 person among transplant recipients is twice the expected rate for the general public.34 Clinical point Screening and appropriate assessment of psychological health should occur at regular intervals, and at least yearly after transplant. Support groups and individual therapy can be a positive resource for patients as it provides an outlet to process a myriad of emotions, including anxiety, depression and survivor’s guilt. They can also deliver a forum for developing positive post-traumatic growth. Pharmacotherapy or referral to psychiatric providers should also be a consideration when clinically indicated. CONFLICT OF INTEREST The authors declare no conflict of interest.

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6 Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21: 389–401. 7 Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2015; 21: 266–274. 8 Rizzo JD, Curtis RE, Socie G, Sobocinski KA, Gilbert E, Landgren O et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2009; 113: 1175–1183. 9 Inamoto Y, Shah NN, Savani BN, Shaw BE, Abraham AA, Ahmed IA et al. Secondary solid cancer screening following hematopoietic cell transplantation. Bone Marrow Transplant 2015; 50: 1013–1023. 10 Savani BN, Griffith ML, Jagasia S, Lee SJ. 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