Curr Hematol Malig Rep (2015) 10:35–44 DOI 10.1007/s11899-014-0243-0
STEM CELL TRANSPLANTATION (R MAZIARZ, SECTION EDITOR)
Survivorship After Allogeneic Transplantation—Management Recommendations for the Primary Care Provider André Tichelli & Alicia Rovó
Published online: 10 February 2015 # Springer Science+Business Media New York 2015
Abstract Prognosis after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved. Therefore, long-term survivorship becomes an important issue. A number of malignant and nonmalignant late effects can cause substantial morbidity, with considerable impact on health and quality of life. The main factors responsible for late effects after HSCT are total body irradiation-based conditioning and chronic graft-versus-host disease and its treatment. The knowledge on late effects serves as guidance for surveillance and management decision. Aftercare includes screening and counseling for prevention and treatment of late complications. The care of HSCT recipients tends with time to be transferred from the transplant center back to the primary care provider, who might not be however familiar with the unique needs of long-term survivors. A broad expertise is needed for the posttransplant management; therefore, transplant centers together with primary care providers should ensure complementary care delivery. Standardized follow-up guidelines on late effects represent the best tool to guaranty good management of long-term survivors. Distribution, broad promotion, and applications of these guidelines are therefore needed.
Keywords Allogeneic hematopoietic stem cell transplantation (HSCT) . Primary care . Aftercare . Prevention . Treatment . Complications
This article is part of the Topical Collection on Stem Cell Transplantation A. Tichelli (*) Division of Hematology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland e-mail: [email protected] A. Rovó Division of Hematology, University Hospital of Bern, Bern, Switzerland
Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a variety of malignant and nonmalignant disorders. Overall survival has improved substantially over the last decades. With the increasing number of HSCT performed yearly worldwide, and the improvement of survival after transplantation, the number of patients surviving 2 years and longer after transplantation is continuously increasing. By 2020, there may be worldwide up to half a million long-term survivors after allogeneic HSCT [1]. Today, cure of the primary disease is no longer the unique aim of the treatment. Recovery of the health status, as it was before the treatment of the primary disease with HSCT, becomes an important issue. This implies recovery of good physical and psychological health, improved quality of life, as well as regular social reinsertion in family and at work. Long-term recipients who have overcome the acute toxicity phase of HSCT and are in remission of their primary disease have completed their treatment and will no longer be considered as patients. Nevertheless, similar to cancer patients, they do not return to pre-diagnosis status [2], and therefore, their health is unlikely to be considered as normal. HSCT remains associated with considerable early and late treatment-related morbidity and mortality. When compared to a matched general population, even decades after transplantation, mortality remains increased [3]. This excess of deaths emerges as an expression of the underlying morbidity affecting this population. The burden of morbidity at 10 years after HSCT is high, with two thirds of the patients having at least one chronic health condition [4]. Even more than 10 years after transplantation, the burden of physical and emotional morbidity in long-term survivors continues to increase. The cumulative incidence of developing any chronic health condition increases up to 71 % and for severe or life-threatening conditions up to 41 % [5••]. Therefore, in order to offer adequate long-term
36
survivorship care, knowledge and expertise on late effects and factors involved are crucial. In this issue, we will focus on late effects that may occur after allogeneic HSCT; discuss the major risk factors involved in late effects; review recommendations on screening, prevention, and early treatment; and discuss the role of the primary care providers in the care of long-term survivors.
Late Effects After Stem Cell Transplantation Late effects are usually divided into malignant and nonmalignant complications. The type and severity of these late effects depend on patient’s characteristics and the involved factors. In theory, any organ can be the target of a nonmalignant late effect, and frequently, multiple causes have contributed. In cancer patients, secondary malignancies are recognized complications of conventional chemotherapy and radiotherapy. They are increasingly identified as a serious complication among HSCT recipients. The estimated risk is reported to be 3.5 % at 10 years, increasing to 12.8 % at 15 years among recipients of allogeneic HSCT. However, not all recipients of HSCT will present all types of complications with similar intensity. In this issue, we will not describe systematically all possible late effects. There are detailed reviews on it [6•, 7]. A list of the most relevant late events is shown in Table 1. Total Body Irradiation and Late Effects Total body irradiation (TBI) was for a long time considered as the main factor involved in the onset of long-term complications. Today, we know that the situation is much more complex. Long-term survivorship after allogeneic HSCT depends on a number of factors: patient’s characteristics at transplantation; the primary disease, its risk category, and the remission state before HSCT; the donor type and source of the graft; the conditioning regimen received for HSCT; and the onset of graft-versus-host disease (GVHD) and its treatment. The therapy received before transplantation also plays an important role. Knowing the factors involved for a given patient, a specific risk profile for long-term management can be established. Indeed, the screening and management program of a recipient conditioned with conventional myeloablative TBI with otherwise an uneventful follow-up post-transplant will not be the same as a patient who was treated with reduced intensity conditioning (RIC), but presents with severe GVHD with a need for extensive treatment with immunosuppressive drugs. Some late complications, for instance cataract formation, infertility, endocrine dysfunction, and secondary nonsquamous tumors, like breast cancer [8], are closely related with TBI conditioning. For instance, the probability to
Curr Hematol Malig Rep (2015) 10:35–44
develop cataracts is dependent on the total radiation dose, the number of radiation fractions, and the dose rate used. The probability of cataract formation is highest after singledose irradiation, intermediate after fractionated irradiation, and lowest after conditioning without TBI. Some nonirradiation factors, mainly the use of steroids over longer periods, may play a causal role as well [9, 10]. The underlying physiopathology for fertility complications seems to be more complicated. Gonadal damage and loss of fertility after HSCT is dependent on the age of the patient at transplantation and the conditioning regimen received for HSCT. In a male cohort, 82 % of patients conditioned with TBI, and only 44 % without TBI, present azoospermia after HSCT [11]. However, despite TBI is the main factor involved in azoospermia, not all irradiated male patients will present definitive infertility, and conversely, patients conditioned without irradiation have nearly 50 % infertility, showing hence the contribution of other factors than TBI. Older age at HSCT, short duration since transplantation, and the presence of chronic GVHD are critical factors in male infertility after HSCT [12]. In female patients, infertility and hypergonadotropic hypogonadism are almost the rule after TBI, with elevated serum FS and LH [13–15]. Girls undergoing HSCT at younger age are those with a better chance to regain their fertility. About 50 % of young girls transplanted before the age of 10 years with conditioning containing fractionated TBI enter puberty spontaneously and experience menarche despite increased LH/FSH levels [16]. Graft-Versus-Host Disease and Late Effects Chronic GVHD is one of the main causes of transplant-related mortality and contributes directly or indirectly to many of the malignant and nonmalignant late effects. Almost all organ systems may be affected; the harmful effect of GVHD on each individual patient can be thus highly variable, affecting one or several organs. In some cases, the manifestations of the GVHD have little impact on the daily activity and do not require any treatment. In other cases, GVHD greatly affects the general health status and adversely impacts patient’s quality of life after HSCT. The profound immune deficiency related with chronic GVHD and its treatment is responsible for most deaths attributable to infection. In some clinical situations, the direct effect of GVHD is obvious. This is the case for instance in the development of bronchiolitis obliterans or dry eye syndrome. In other late effects, it is not possible to distinguish between what gives rise to the complication, GVHD or its treatment. Chronic kidney disease and avascular necrosis of the bone are two late effects demonstrating this inextricable relationship. Among 1190 long-term adult patients who underwent HSCT and survived for at least 1 year, the estimated cumulative incidence of chronic kidney disease was 5.7 % at 10 years after HSCT. Older age at transplantation, exposure
Local irradiation TBI
Cranial irradiation TBI
TBI Older age
Chronic GVHD TBI
Anthracyclines
TBI and GVHD Dyslipidemia, diabetes, chronic kidney disease, hypertension, smoking, and physical inactivity Calcineurin inhibitors Chronic GVHD
HCV infection Iron overload
Thyroid dysfunction
Growth failure
Fertility and gonadal failure
Respiratory tract complications
Cardiac complications
Vascular complications
Liver complications
TBI
HLA disparity Donor source
GVHD— infections
Renal complications
Main risk factors
Check blood pressure, serum creatinine and glomerular filtration rate, and urine sediment Check for proteinuria Liver function testing HCV monitoring during treatment Ferritin Liver biopsy in patients at risk MRI if necessary
Check blood pressure Weight (BMI) Lipidogram Glucose tolerance
Monitor growth velocity (particular pubertal growth) Growth hormone (repetitive if abnormal growth) FSH and LH Testosterone in males Seminal fluid analysis post-HSCT in males Clinical assessment Pulmonary function tests Radiographic evaluation if indicated Check blood pressure, cardiac rhythm, and cardiac function
Clinical assessment Blood count Lymphocyte subsets Immunoglobulin levels CMV monitoring TSH and fT3
Screening
Importance of compliance of treatment (HCV infection)
Healthy heart lifestyle Regular exercise Compliance for the treatment/ prevention cardiovascular risk factors Suspend nephrotoxic drugs whenever possible
Avoiding of smoking Vaccination schedule
High likelihood of post-HSCT infertility Contraception if indicated
During childhood and adolescence, regular controls are mandatory
Vaccination schedule Consider functional asplenia
Counseling
Consider pegylated-IFN alpha and ribavirin treatment in HCV infection
Phlebotomy or iron chelation
Treatment of pain
Dialysis Renal transplantation
Steroids and bronchodilators Treatment of GVHD Treatment of infections Pacemaker Surgical intervention if indicated Transplantation (?) Surgical intervention if indicated
Hormonal substitution if indicated
Substitution with Lthyroxin in overt hypothyroidism Growth hormone treatment if indicated according to an endocrinologist
Always indicated if a pathogen has been identified
Treatment
Adapt dosage of calcineurin inhibitors Choose alternative
Early treatment of cardiovascular risk factors
Avoiding risk of a viral infection (influenza, RSV, etc.)
Cryopreservation of sperms Embryo or oocyte banking
Fractionation of TBI if irradiation is indicated Timing of puberty induction
Antibiotic prophylaxis PCP prophylaxis
Prevention
List of the most important late effects after allogeneic hematopoietic stem cell transplantation, with risk factors, screening, patient’s counseling, prevention, and treatment [44]
Late effects
Table 1
Curr Hematol Malig Rep (2015) 10:35–44 37
Prolonged steroid treatment GVHD
TBI Prolonged steroid treatment Calcineurin inhibitors Inactivity Gonadal failure TBI Steroids GVHD Irradiation Infection
Avascular necrosis
Osteoporosis
Clinical assessment MRI Electromyography CNS or nerve biopsy
TBI Cranial radiation therapy Intrathecal chemotherapy GVHD Pre-transplant chemotherapy and radiation therapy TBI TBI Fludarabine (?) Pre-transplant radiation therapy
Nonsquamous cell carcinoma - Breast cancer - Thyroid cancer
Malignant hematological neoplasms
Clinical assessment
GVHD
Complications of the skin and appendages Central and peripheral system complications
Mammography in females Ultrasonography of the thyroid gland
Blood counts and smears Chimerism analysis of normal/malignant cells
Clinical assessment Cervical cytology
GVHD Peripheral blood stem cells
Genital tract complications
Clinical assessment Dental assessment
GVHD Irradiation Poor oral hygiene
Ophthalmologic assessment Schirmer testing
Split lamp
Bone density measurement
Screening
Oral complication
Kerato-conjunctivitis
Cataract formation
Main risk factors
Late effects
Table 1 (continued)
Self-examination of breast, skin, and mucosa Regular clinical assessment
Self-examination of the skin
Instruction regarding sicca Importance of oral hygiene Regular dental assessment Avoidance of sugar-containing drinks Self-surveillance Instruction on early recognition of symptoms, on importance of genital hygiene, and on the use of vaginal dilatators
Instructions regarding sicca
Regular physical activity
Counseling
Treatment
Teeth brushing with fluoride-containing toothpaste Remineralization solutions Topical application of immunosuppressive agents Use of vaginal dilator Systemic estrogen and progesterone replacement Skin inspection for cancer
Fractionation of TBI if irradiation indicated Artificial tears
Early treatment of the cancer
Treatment of infection Adapt dosage of calcineurin inhibitors Choose an alternative in case of toxicity Treatment of the malignant disease
Topical treatment Treatment of GVHD
Treatment of local infections Surgical therapy if indicated
Local therapy with steroids and/or cyclosporine Systemic therapy of GVHD Treatment of GVHD
Surgical repair
Avoidance of longOrthopedic measures term treatment with Surgical repair corticosteroids Sex hormone substitution Treatment of bone Bisphosphonates fractures Avoidance of long-term treatment with corticosteroids
Prevention
38 Curr Hematol Malig Rep (2015) 10:35–44
Psychological support Pharmaceutical support
to calcineurin inhibitors for GVHD prophylaxis or treatment, and the use of nephrotoxic drugs were the main risk factors [17]. In another large cohort study of 1635 patients treated with HSCT, a strong association was observed between acute and chronic GVHD and renal dysfunction [18]. Avascular necrosis of the bone is a well-reported late complication after HSCT, causing significant morbidity. The joint most often involved is the hip, with bilateral involvement in more than half of the patients. More than one third of the patients will require joint replacement [19]. The cumulative incidence of avascular bone necrosis at 10 years is 4 % after autologous HSCT, 6 % after allogeneic sibling donor HSCT, and 15 % after unrelated donor HSCT. Among allogeneic HSCT recipients, the risk is increased in male patients, those diagnosed with chronic GVHD, or those exposed to at least three immunosuppressive drugs [20]. Cardiovascular Disease and Late Effects
GVHD graft-versus-host disease, TBI total body irradiation, BMI body mass index
GVHD late effects
Regular clinical controls
Squamous cell carcinoma of the oral cavity Performance, quality of life, and sexuality
Younger age Longer follow-up GVHD - Colon cancers
Inquiries about general performance, social and familial life, depression, fatigue, and sexual function
Self-examination of the oral mucosa Regular clinical assessment Counseling by specialist of the recipient, involving partner and family
Prevention Counseling Screening Main risk factors Late effects
Table 1 (continued)
39
Consider lifestyle Rapid reinsertion in professional life Consider nonpharmaceutical measures
Treatment
Early treatment of the cancer
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Cardiovascular diseases have become an emerging late complication in patients treated with HSCT. For long time, cardiovascular complications have not been considered belonging to the late effects of HSCT. The frequent prevalence of vascular diseases in the general population and its late appearance after HSCT were the major confounding factors for the delayed recognition. Today, the increased risk of vascular events after allogeneic HSCT and its premature appearance at a younger age has been definitively established [21]. In a retrospective study, the cumulative incidence of cardiovascular diseases after HSCT was 22 % at 25 years. Adjusted for age of the patients, recipients of allogeneic HSCT presented significantly more vascular events than patients treated with autologous HSCT [22]. In a recent publication on 1491 long-term survivors, transplant recipients experienced higher cardiovascular deaths and showed increased cumulative incidence of ischemic heart disease, cardiomyopathy, heart failure, stroke, and rhythm disorders, when compared to a matched control cohort [23]. A number of pre- and post-transplant factors may contribute to accelerated atherosclerosis leading later to cardiovascular disease. An unequivocal relationship between posttransplant cardiovascular risk factors and cardiovascular disease in HSCT long-term survivors has been demonstrated [21, 22]. Hypertension, diabetes, and dyslipidemia appearing after HSCT, as well as physical inactivity and ongoing tobacco smoking, were related with increased risk of late cardiovascular diseases. Patients presenting more than 50 % of these risk factors after HSCT had a cumulative incidence of a cardiovascular complication at 15 years of 17 %, compared to 4 % for patients with less risk factors present. Endothelial injury occurring during HSCT conditioning and damage by GVHD might contribute to premature cardiovascular diseases in this cohort. The role of radiation therapy on vascular complications has already been demonstrated in patients with Hodgkin
40
diseases treated with chemotherapy and mediastinal radiotherapy; these patients had a twofold to sevenfold increased risk of myocardial infarction, angina pectoris, and congestive heart failure [24]. There are a number of studies showing that cardiovascular risk factors including metabolic syndrome appear more frequently after allogeneic HSCT. In a large cohort of 1089 HSCT recipients who survived at least 2 years and were not currently taking immunosuppressant agents, the prevalence of diabetes, hypertension, and dyslipidemia was increased, as compared to siblings [25, 26]. This risk was even higher for patients conditioned with TBI. Cardiovascular risk factors were shown to be increased after allogeneic HSCT compared to autologous HSCT, with a relative risk of new onset for hypertension, diabetes, and dyslipidemia of 5.2, 2.6, and 2.2, respectively [27]. The reason why HSCT long-term survivors develop more frequently cardiovascular risk factors still needs to be clarified. However, endocrine dysfunctions, with growth hormone insufficiency, hypothyroidism, and particularly gonadal dysfunction, might play a role. Despite reporting healthier lifestyle behavior than the general population, HSCT survivors continue to have a greater burden of cardiovascular conditions, as a consequence of pre-transplant and transplant-related exposure. However, attention of clinicians to conventional cardiovascular risk factors and modifiable lifestyle characteristics offers hope of reducing cardiovascular morbidity after allogeneic HSCT. Controlling dyslipidemia, hypertension, and diabetes in recipients of HSCT was associated with a reduction of serious cardiovascular outcomes. Potential influence of abstention of smoking, healthy diet, and regular physical activity was also present, but more modest [28•]. Reduced Intensity Conditioning and Late Effects Changes in the practice of HSCT regarding the conditioning regimen and the post-transplant procedure will affect the pattern of late effects. However, the consequences of these changes will appear with a delay of years or even decades. The most important changes during the last 10 years which could have, in the future, an influence on long-term survivorship are the progressive reduction of the conditioning with TBI and the introduction of RIC. RIC offers the possibility of HSCT to elderly patients and to younger patients with comorbidity. The available data suggest that RIC provides similar donor engraftment and risk of GVHD, increased probability of relapse, and decreased transplant-related mortality [29]. There are still few data on long-term outcome of patients treated with RIC. However, we can postulate that late effects due to toxicity of the treatment will be reduced, while those related to GVHD and its treatment will be unchanged when compared to patients who received myeloablative conditioning. However, in addition to these hypothetical considerations,
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new factors of undetermined relevance, such as older age, higher rates of comorbidity, or the use of fludarabine for conditioning, might generate a complete new landscape in respect of late effects. Quality of Life and Time of Appearance of Late Effects Late effects, although often not life threatening, significantly impair the quality of life in long-term survivors. Despite that quality of life is generally perceived as satisfactory to good in a majority of long-term survivors after HSCT, fatigue and sleeping disorders have been reported in up to 65 % of patients and may persist over years after transplantation [30, 31]. Physical health but not mental health was significantly lower in patients with extensive chronic GVHD, as compared to their matched sibling donor [32]. Concerns about sexuality have been reported in approximately 25 % of patients. Health and quality of life do not necessarily correlate. Some patients with more advanced disease report better quality of life after transplantation than patients with less late effects. Quality of life is subjective and reflects the patient feelings and expectations of health, while health corresponds to an objective assessment of the situation. Coping strategies of some patients with late effects may lead to lower self-perception of illness and therefore improve their quality of life. The time of appearance of a late complication can greatly vary. Some of the complications can appear within the first year after HSCT but have relevant long-term consequences for the recipient. Many long-term complications appear within the first 10 years. However, bronchiolitis obliterans appears usually within the first 6 months after transplantation, and cardiovascular diseases or secondary solid tumors occur often decades after HSCT. Therefore, life-long surveillance of longterm survivors after allogeneic HSCT is mandatory.
Management of Long-Term Survivors After Allogeneic HSCT The experience collected during the past decades has become the main source of information on long-term survivorship after HSCT. This knowledge on late effects should serve as guidance for the current management of long-term survivors. Post-transplant care guidelines are now available and include recommendations for long-term post-transplant screening and preventive practices, screening for chronic GVHD, and vaccinations. The recommendations provided by the National Marrow Donor Program (NMDP) are based on the Recommended Screening and Preventive Practices, developed by experts from seven international transplant professional societies. They were first published in 2006 [33] and updated in 2012 [34••] and are intended to help both onco-
Curr Hematol Malig Rep (2015) 10:35–44
hematologists and primary care providers in addressing the medical and psychological needs of survivors after HSCT [35•]. A broad medical expertise is necessary to manage longterm survivors. The magnitude of risk and the severity of the late complications may greatly vary between individual patients. Therefore, the follow-up care should be individualized, based on the patient’s history and its risk factors for long-term complications. Aftercare of long-term survivors includes a standardized screening, counseling of the patient, as well as prevention and treatment of late effects. Counseling should include self-examination for early cancer detection, adherence to medication, and advices for healthy lifestyle behavior (Table 2). High-risk health behaviors such as current smoking, risky alcohol intake, and unhealthy diet should be avoided. Compared to their siblings, HSCT survivors are more likely to indulge in high-risk behavior. However, patients younger than 35 years of age and those with lower educational status were more likely to demonstrate high-risk behavior [36]. Adherence and Health-Care Utilization Nonadherence in outpatient care may compromise treatment effectiveness and place the patient at increased risk for treatment failure. More complex medical regimens are associated with poorer adherence [37]. As for other chronic diseases, adolescents are of particular risk for nonadherence. In a small study on six adolescents who had undergone HSCT, the participants demonstrated considerable nonadherence; they were taking an average of 73 % of prescribed doses and had a perfect adherence in less than four of seven days per week [38]. This behavior exposes patients to treatment failure. Problematic adherence after HSCT has been shown to be associated with increased likelihood of HSCT-related mortality among adults [39]. The need for long-term surveillance has been recognized and is now universally accepted by the transplant community. However, health-care utilization by long-term HSCT survivors at risk for late effects is critical. Less than one third of the recipients surviving ≥10 years regularly visit a specialist confident on long-term complications [5]. Many survivors are no longer under the care of transplant centers. In a cohort of 845 long-term survivors, 98 % of allogeneic HSCT recipients reported medical contact after transplantation. While cancerrelated visits decreased with time from HSCT, the prevalence of general physical examinations increased [40]. Provider of Care for Long-Term Survivors After HSCT Who should be responsible for the long-term care of HSCT survivors? Transplant centers have traditionally assumed responsibility for hematological and primary care health in transplanted patients. Today, long-term HSCT recipients are no longer under the care of the transplant center. Most of them
41 Table 2 Checklist of recommendations for counseling of the long-term survivor during the follow-up visit, according to the recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation [43] 1. Healthy heart lifestyle recommendations a. Eat a healthy diet with a wide variety of foods b. Do not smoke (passive and active exposure), and check tobacco illegal drug use. For smokers, insist on smoking cessation c. Use alcohol in moderation, generally
STEM CELL TRANSPLANTATION (R MAZIARZ, SECTION EDITOR)
Survivorship After Allogeneic Transplantation—Management Recommendations for the Primary Care Provider André Tichelli & Alicia Rovó
Published online: 10 February 2015 # Springer Science+Business Media New York 2015
Abstract Prognosis after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved. Therefore, long-term survivorship becomes an important issue. A number of malignant and nonmalignant late effects can cause substantial morbidity, with considerable impact on health and quality of life. The main factors responsible for late effects after HSCT are total body irradiation-based conditioning and chronic graft-versus-host disease and its treatment. The knowledge on late effects serves as guidance for surveillance and management decision. Aftercare includes screening and counseling for prevention and treatment of late complications. The care of HSCT recipients tends with time to be transferred from the transplant center back to the primary care provider, who might not be however familiar with the unique needs of long-term survivors. A broad expertise is needed for the posttransplant management; therefore, transplant centers together with primary care providers should ensure complementary care delivery. Standardized follow-up guidelines on late effects represent the best tool to guaranty good management of long-term survivors. Distribution, broad promotion, and applications of these guidelines are therefore needed.
Keywords Allogeneic hematopoietic stem cell transplantation (HSCT) . Primary care . Aftercare . Prevention . Treatment . Complications
This article is part of the Topical Collection on Stem Cell Transplantation A. Tichelli (*) Division of Hematology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland e-mail: [email protected] A. Rovó Division of Hematology, University Hospital of Bern, Bern, Switzerland
Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a variety of malignant and nonmalignant disorders. Overall survival has improved substantially over the last decades. With the increasing number of HSCT performed yearly worldwide, and the improvement of survival after transplantation, the number of patients surviving 2 years and longer after transplantation is continuously increasing. By 2020, there may be worldwide up to half a million long-term survivors after allogeneic HSCT [1]. Today, cure of the primary disease is no longer the unique aim of the treatment. Recovery of the health status, as it was before the treatment of the primary disease with HSCT, becomes an important issue. This implies recovery of good physical and psychological health, improved quality of life, as well as regular social reinsertion in family and at work. Long-term recipients who have overcome the acute toxicity phase of HSCT and are in remission of their primary disease have completed their treatment and will no longer be considered as patients. Nevertheless, similar to cancer patients, they do not return to pre-diagnosis status [2], and therefore, their health is unlikely to be considered as normal. HSCT remains associated with considerable early and late treatment-related morbidity and mortality. When compared to a matched general population, even decades after transplantation, mortality remains increased [3]. This excess of deaths emerges as an expression of the underlying morbidity affecting this population. The burden of morbidity at 10 years after HSCT is high, with two thirds of the patients having at least one chronic health condition [4]. Even more than 10 years after transplantation, the burden of physical and emotional morbidity in long-term survivors continues to increase. The cumulative incidence of developing any chronic health condition increases up to 71 % and for severe or life-threatening conditions up to 41 % [5••]. Therefore, in order to offer adequate long-term
36
survivorship care, knowledge and expertise on late effects and factors involved are crucial. In this issue, we will focus on late effects that may occur after allogeneic HSCT; discuss the major risk factors involved in late effects; review recommendations on screening, prevention, and early treatment; and discuss the role of the primary care providers in the care of long-term survivors.
Late Effects After Stem Cell Transplantation Late effects are usually divided into malignant and nonmalignant complications. The type and severity of these late effects depend on patient’s characteristics and the involved factors. In theory, any organ can be the target of a nonmalignant late effect, and frequently, multiple causes have contributed. In cancer patients, secondary malignancies are recognized complications of conventional chemotherapy and radiotherapy. They are increasingly identified as a serious complication among HSCT recipients. The estimated risk is reported to be 3.5 % at 10 years, increasing to 12.8 % at 15 years among recipients of allogeneic HSCT. However, not all recipients of HSCT will present all types of complications with similar intensity. In this issue, we will not describe systematically all possible late effects. There are detailed reviews on it [6•, 7]. A list of the most relevant late events is shown in Table 1. Total Body Irradiation and Late Effects Total body irradiation (TBI) was for a long time considered as the main factor involved in the onset of long-term complications. Today, we know that the situation is much more complex. Long-term survivorship after allogeneic HSCT depends on a number of factors: patient’s characteristics at transplantation; the primary disease, its risk category, and the remission state before HSCT; the donor type and source of the graft; the conditioning regimen received for HSCT; and the onset of graft-versus-host disease (GVHD) and its treatment. The therapy received before transplantation also plays an important role. Knowing the factors involved for a given patient, a specific risk profile for long-term management can be established. Indeed, the screening and management program of a recipient conditioned with conventional myeloablative TBI with otherwise an uneventful follow-up post-transplant will not be the same as a patient who was treated with reduced intensity conditioning (RIC), but presents with severe GVHD with a need for extensive treatment with immunosuppressive drugs. Some late complications, for instance cataract formation, infertility, endocrine dysfunction, and secondary nonsquamous tumors, like breast cancer [8], are closely related with TBI conditioning. For instance, the probability to
Curr Hematol Malig Rep (2015) 10:35–44
develop cataracts is dependent on the total radiation dose, the number of radiation fractions, and the dose rate used. The probability of cataract formation is highest after singledose irradiation, intermediate after fractionated irradiation, and lowest after conditioning without TBI. Some nonirradiation factors, mainly the use of steroids over longer periods, may play a causal role as well [9, 10]. The underlying physiopathology for fertility complications seems to be more complicated. Gonadal damage and loss of fertility after HSCT is dependent on the age of the patient at transplantation and the conditioning regimen received for HSCT. In a male cohort, 82 % of patients conditioned with TBI, and only 44 % without TBI, present azoospermia after HSCT [11]. However, despite TBI is the main factor involved in azoospermia, not all irradiated male patients will present definitive infertility, and conversely, patients conditioned without irradiation have nearly 50 % infertility, showing hence the contribution of other factors than TBI. Older age at HSCT, short duration since transplantation, and the presence of chronic GVHD are critical factors in male infertility after HSCT [12]. In female patients, infertility and hypergonadotropic hypogonadism are almost the rule after TBI, with elevated serum FS and LH [13–15]. Girls undergoing HSCT at younger age are those with a better chance to regain their fertility. About 50 % of young girls transplanted before the age of 10 years with conditioning containing fractionated TBI enter puberty spontaneously and experience menarche despite increased LH/FSH levels [16]. Graft-Versus-Host Disease and Late Effects Chronic GVHD is one of the main causes of transplant-related mortality and contributes directly or indirectly to many of the malignant and nonmalignant late effects. Almost all organ systems may be affected; the harmful effect of GVHD on each individual patient can be thus highly variable, affecting one or several organs. In some cases, the manifestations of the GVHD have little impact on the daily activity and do not require any treatment. In other cases, GVHD greatly affects the general health status and adversely impacts patient’s quality of life after HSCT. The profound immune deficiency related with chronic GVHD and its treatment is responsible for most deaths attributable to infection. In some clinical situations, the direct effect of GVHD is obvious. This is the case for instance in the development of bronchiolitis obliterans or dry eye syndrome. In other late effects, it is not possible to distinguish between what gives rise to the complication, GVHD or its treatment. Chronic kidney disease and avascular necrosis of the bone are two late effects demonstrating this inextricable relationship. Among 1190 long-term adult patients who underwent HSCT and survived for at least 1 year, the estimated cumulative incidence of chronic kidney disease was 5.7 % at 10 years after HSCT. Older age at transplantation, exposure
Local irradiation TBI
Cranial irradiation TBI
TBI Older age
Chronic GVHD TBI
Anthracyclines
TBI and GVHD Dyslipidemia, diabetes, chronic kidney disease, hypertension, smoking, and physical inactivity Calcineurin inhibitors Chronic GVHD
HCV infection Iron overload
Thyroid dysfunction
Growth failure
Fertility and gonadal failure
Respiratory tract complications
Cardiac complications
Vascular complications
Liver complications
TBI
HLA disparity Donor source
GVHD— infections
Renal complications
Main risk factors
Check blood pressure, serum creatinine and glomerular filtration rate, and urine sediment Check for proteinuria Liver function testing HCV monitoring during treatment Ferritin Liver biopsy in patients at risk MRI if necessary
Check blood pressure Weight (BMI) Lipidogram Glucose tolerance
Monitor growth velocity (particular pubertal growth) Growth hormone (repetitive if abnormal growth) FSH and LH Testosterone in males Seminal fluid analysis post-HSCT in males Clinical assessment Pulmonary function tests Radiographic evaluation if indicated Check blood pressure, cardiac rhythm, and cardiac function
Clinical assessment Blood count Lymphocyte subsets Immunoglobulin levels CMV monitoring TSH and fT3
Screening
Importance of compliance of treatment (HCV infection)
Healthy heart lifestyle Regular exercise Compliance for the treatment/ prevention cardiovascular risk factors Suspend nephrotoxic drugs whenever possible
Avoiding of smoking Vaccination schedule
High likelihood of post-HSCT infertility Contraception if indicated
During childhood and adolescence, regular controls are mandatory
Vaccination schedule Consider functional asplenia
Counseling
Consider pegylated-IFN alpha and ribavirin treatment in HCV infection
Phlebotomy or iron chelation
Treatment of pain
Dialysis Renal transplantation
Steroids and bronchodilators Treatment of GVHD Treatment of infections Pacemaker Surgical intervention if indicated Transplantation (?) Surgical intervention if indicated
Hormonal substitution if indicated
Substitution with Lthyroxin in overt hypothyroidism Growth hormone treatment if indicated according to an endocrinologist
Always indicated if a pathogen has been identified
Treatment
Adapt dosage of calcineurin inhibitors Choose alternative
Early treatment of cardiovascular risk factors
Avoiding risk of a viral infection (influenza, RSV, etc.)
Cryopreservation of sperms Embryo or oocyte banking
Fractionation of TBI if irradiation is indicated Timing of puberty induction
Antibiotic prophylaxis PCP prophylaxis
Prevention
List of the most important late effects after allogeneic hematopoietic stem cell transplantation, with risk factors, screening, patient’s counseling, prevention, and treatment [44]
Late effects
Table 1
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Prolonged steroid treatment GVHD
TBI Prolonged steroid treatment Calcineurin inhibitors Inactivity Gonadal failure TBI Steroids GVHD Irradiation Infection
Avascular necrosis
Osteoporosis
Clinical assessment MRI Electromyography CNS or nerve biopsy
TBI Cranial radiation therapy Intrathecal chemotherapy GVHD Pre-transplant chemotherapy and radiation therapy TBI TBI Fludarabine (?) Pre-transplant radiation therapy
Nonsquamous cell carcinoma - Breast cancer - Thyroid cancer
Malignant hematological neoplasms
Clinical assessment
GVHD
Complications of the skin and appendages Central and peripheral system complications
Mammography in females Ultrasonography of the thyroid gland
Blood counts and smears Chimerism analysis of normal/malignant cells
Clinical assessment Cervical cytology
GVHD Peripheral blood stem cells
Genital tract complications
Clinical assessment Dental assessment
GVHD Irradiation Poor oral hygiene
Ophthalmologic assessment Schirmer testing
Split lamp
Bone density measurement
Screening
Oral complication
Kerato-conjunctivitis
Cataract formation
Main risk factors
Late effects
Table 1 (continued)
Self-examination of breast, skin, and mucosa Regular clinical assessment
Self-examination of the skin
Instruction regarding sicca Importance of oral hygiene Regular dental assessment Avoidance of sugar-containing drinks Self-surveillance Instruction on early recognition of symptoms, on importance of genital hygiene, and on the use of vaginal dilatators
Instructions regarding sicca
Regular physical activity
Counseling
Treatment
Teeth brushing with fluoride-containing toothpaste Remineralization solutions Topical application of immunosuppressive agents Use of vaginal dilator Systemic estrogen and progesterone replacement Skin inspection for cancer
Fractionation of TBI if irradiation indicated Artificial tears
Early treatment of the cancer
Treatment of infection Adapt dosage of calcineurin inhibitors Choose an alternative in case of toxicity Treatment of the malignant disease
Topical treatment Treatment of GVHD
Treatment of local infections Surgical therapy if indicated
Local therapy with steroids and/or cyclosporine Systemic therapy of GVHD Treatment of GVHD
Surgical repair
Avoidance of longOrthopedic measures term treatment with Surgical repair corticosteroids Sex hormone substitution Treatment of bone Bisphosphonates fractures Avoidance of long-term treatment with corticosteroids
Prevention
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Psychological support Pharmaceutical support
to calcineurin inhibitors for GVHD prophylaxis or treatment, and the use of nephrotoxic drugs were the main risk factors [17]. In another large cohort study of 1635 patients treated with HSCT, a strong association was observed between acute and chronic GVHD and renal dysfunction [18]. Avascular necrosis of the bone is a well-reported late complication after HSCT, causing significant morbidity. The joint most often involved is the hip, with bilateral involvement in more than half of the patients. More than one third of the patients will require joint replacement [19]. The cumulative incidence of avascular bone necrosis at 10 years is 4 % after autologous HSCT, 6 % after allogeneic sibling donor HSCT, and 15 % after unrelated donor HSCT. Among allogeneic HSCT recipients, the risk is increased in male patients, those diagnosed with chronic GVHD, or those exposed to at least three immunosuppressive drugs [20]. Cardiovascular Disease and Late Effects
GVHD graft-versus-host disease, TBI total body irradiation, BMI body mass index
GVHD late effects
Regular clinical controls
Squamous cell carcinoma of the oral cavity Performance, quality of life, and sexuality
Younger age Longer follow-up GVHD - Colon cancers
Inquiries about general performance, social and familial life, depression, fatigue, and sexual function
Self-examination of the oral mucosa Regular clinical assessment Counseling by specialist of the recipient, involving partner and family
Prevention Counseling Screening Main risk factors Late effects
Table 1 (continued)
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Consider lifestyle Rapid reinsertion in professional life Consider nonpharmaceutical measures
Treatment
Early treatment of the cancer
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Cardiovascular diseases have become an emerging late complication in patients treated with HSCT. For long time, cardiovascular complications have not been considered belonging to the late effects of HSCT. The frequent prevalence of vascular diseases in the general population and its late appearance after HSCT were the major confounding factors for the delayed recognition. Today, the increased risk of vascular events after allogeneic HSCT and its premature appearance at a younger age has been definitively established [21]. In a retrospective study, the cumulative incidence of cardiovascular diseases after HSCT was 22 % at 25 years. Adjusted for age of the patients, recipients of allogeneic HSCT presented significantly more vascular events than patients treated with autologous HSCT [22]. In a recent publication on 1491 long-term survivors, transplant recipients experienced higher cardiovascular deaths and showed increased cumulative incidence of ischemic heart disease, cardiomyopathy, heart failure, stroke, and rhythm disorders, when compared to a matched control cohort [23]. A number of pre- and post-transplant factors may contribute to accelerated atherosclerosis leading later to cardiovascular disease. An unequivocal relationship between posttransplant cardiovascular risk factors and cardiovascular disease in HSCT long-term survivors has been demonstrated [21, 22]. Hypertension, diabetes, and dyslipidemia appearing after HSCT, as well as physical inactivity and ongoing tobacco smoking, were related with increased risk of late cardiovascular diseases. Patients presenting more than 50 % of these risk factors after HSCT had a cumulative incidence of a cardiovascular complication at 15 years of 17 %, compared to 4 % for patients with less risk factors present. Endothelial injury occurring during HSCT conditioning and damage by GVHD might contribute to premature cardiovascular diseases in this cohort. The role of radiation therapy on vascular complications has already been demonstrated in patients with Hodgkin
40
diseases treated with chemotherapy and mediastinal radiotherapy; these patients had a twofold to sevenfold increased risk of myocardial infarction, angina pectoris, and congestive heart failure [24]. There are a number of studies showing that cardiovascular risk factors including metabolic syndrome appear more frequently after allogeneic HSCT. In a large cohort of 1089 HSCT recipients who survived at least 2 years and were not currently taking immunosuppressant agents, the prevalence of diabetes, hypertension, and dyslipidemia was increased, as compared to siblings [25, 26]. This risk was even higher for patients conditioned with TBI. Cardiovascular risk factors were shown to be increased after allogeneic HSCT compared to autologous HSCT, with a relative risk of new onset for hypertension, diabetes, and dyslipidemia of 5.2, 2.6, and 2.2, respectively [27]. The reason why HSCT long-term survivors develop more frequently cardiovascular risk factors still needs to be clarified. However, endocrine dysfunctions, with growth hormone insufficiency, hypothyroidism, and particularly gonadal dysfunction, might play a role. Despite reporting healthier lifestyle behavior than the general population, HSCT survivors continue to have a greater burden of cardiovascular conditions, as a consequence of pre-transplant and transplant-related exposure. However, attention of clinicians to conventional cardiovascular risk factors and modifiable lifestyle characteristics offers hope of reducing cardiovascular morbidity after allogeneic HSCT. Controlling dyslipidemia, hypertension, and diabetes in recipients of HSCT was associated with a reduction of serious cardiovascular outcomes. Potential influence of abstention of smoking, healthy diet, and regular physical activity was also present, but more modest [28•]. Reduced Intensity Conditioning and Late Effects Changes in the practice of HSCT regarding the conditioning regimen and the post-transplant procedure will affect the pattern of late effects. However, the consequences of these changes will appear with a delay of years or even decades. The most important changes during the last 10 years which could have, in the future, an influence on long-term survivorship are the progressive reduction of the conditioning with TBI and the introduction of RIC. RIC offers the possibility of HSCT to elderly patients and to younger patients with comorbidity. The available data suggest that RIC provides similar donor engraftment and risk of GVHD, increased probability of relapse, and decreased transplant-related mortality [29]. There are still few data on long-term outcome of patients treated with RIC. However, we can postulate that late effects due to toxicity of the treatment will be reduced, while those related to GVHD and its treatment will be unchanged when compared to patients who received myeloablative conditioning. However, in addition to these hypothetical considerations,
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new factors of undetermined relevance, such as older age, higher rates of comorbidity, or the use of fludarabine for conditioning, might generate a complete new landscape in respect of late effects. Quality of Life and Time of Appearance of Late Effects Late effects, although often not life threatening, significantly impair the quality of life in long-term survivors. Despite that quality of life is generally perceived as satisfactory to good in a majority of long-term survivors after HSCT, fatigue and sleeping disorders have been reported in up to 65 % of patients and may persist over years after transplantation [30, 31]. Physical health but not mental health was significantly lower in patients with extensive chronic GVHD, as compared to their matched sibling donor [32]. Concerns about sexuality have been reported in approximately 25 % of patients. Health and quality of life do not necessarily correlate. Some patients with more advanced disease report better quality of life after transplantation than patients with less late effects. Quality of life is subjective and reflects the patient feelings and expectations of health, while health corresponds to an objective assessment of the situation. Coping strategies of some patients with late effects may lead to lower self-perception of illness and therefore improve their quality of life. The time of appearance of a late complication can greatly vary. Some of the complications can appear within the first year after HSCT but have relevant long-term consequences for the recipient. Many long-term complications appear within the first 10 years. However, bronchiolitis obliterans appears usually within the first 6 months after transplantation, and cardiovascular diseases or secondary solid tumors occur often decades after HSCT. Therefore, life-long surveillance of longterm survivors after allogeneic HSCT is mandatory.
Management of Long-Term Survivors After Allogeneic HSCT The experience collected during the past decades has become the main source of information on long-term survivorship after HSCT. This knowledge on late effects should serve as guidance for the current management of long-term survivors. Post-transplant care guidelines are now available and include recommendations for long-term post-transplant screening and preventive practices, screening for chronic GVHD, and vaccinations. The recommendations provided by the National Marrow Donor Program (NMDP) are based on the Recommended Screening and Preventive Practices, developed by experts from seven international transplant professional societies. They were first published in 2006 [33] and updated in 2012 [34••] and are intended to help both onco-
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hematologists and primary care providers in addressing the medical and psychological needs of survivors after HSCT [35•]. A broad medical expertise is necessary to manage longterm survivors. The magnitude of risk and the severity of the late complications may greatly vary between individual patients. Therefore, the follow-up care should be individualized, based on the patient’s history and its risk factors for long-term complications. Aftercare of long-term survivors includes a standardized screening, counseling of the patient, as well as prevention and treatment of late effects. Counseling should include self-examination for early cancer detection, adherence to medication, and advices for healthy lifestyle behavior (Table 2). High-risk health behaviors such as current smoking, risky alcohol intake, and unhealthy diet should be avoided. Compared to their siblings, HSCT survivors are more likely to indulge in high-risk behavior. However, patients younger than 35 years of age and those with lower educational status were more likely to demonstrate high-risk behavior [36]. Adherence and Health-Care Utilization Nonadherence in outpatient care may compromise treatment effectiveness and place the patient at increased risk for treatment failure. More complex medical regimens are associated with poorer adherence [37]. As for other chronic diseases, adolescents are of particular risk for nonadherence. In a small study on six adolescents who had undergone HSCT, the participants demonstrated considerable nonadherence; they were taking an average of 73 % of prescribed doses and had a perfect adherence in less than four of seven days per week [38]. This behavior exposes patients to treatment failure. Problematic adherence after HSCT has been shown to be associated with increased likelihood of HSCT-related mortality among adults [39]. The need for long-term surveillance has been recognized and is now universally accepted by the transplant community. However, health-care utilization by long-term HSCT survivors at risk for late effects is critical. Less than one third of the recipients surviving ≥10 years regularly visit a specialist confident on long-term complications [5]. Many survivors are no longer under the care of transplant centers. In a cohort of 845 long-term survivors, 98 % of allogeneic HSCT recipients reported medical contact after transplantation. While cancerrelated visits decreased with time from HSCT, the prevalence of general physical examinations increased [40]. Provider of Care for Long-Term Survivors After HSCT Who should be responsible for the long-term care of HSCT survivors? Transplant centers have traditionally assumed responsibility for hematological and primary care health in transplanted patients. Today, long-term HSCT recipients are no longer under the care of the transplant center. Most of them
41 Table 2 Checklist of recommendations for counseling of the long-term survivor during the follow-up visit, according to the recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation [43] 1. Healthy heart lifestyle recommendations a. Eat a healthy diet with a wide variety of foods b. Do not smoke (passive and active exposure), and check tobacco illegal drug use. For smokers, insist on smoking cessation c. Use alcohol in moderation, generally
