CHAPTER 12. Long term survivorship, general health status, quality of life and late complications after HSCT. A. Tichelli, C-P. Schwarze, G.

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1 EBMT2008_1_21:EBMT :17 Pagina 236 * CHAPTER 12 Long term survivorship, general health status, quality of life and late complications after HSCT A. Tichelli, C-P. Schwarze, G. Socié

2 EBMT2008_1_21:EBMT :17 Pagina 237 CHAPTER 12 Late effects 1. Introduction Large numbers of patients now survive long term following haematopoietic stem cell transplantation (HSCT). The aim of HSCT is not only to cure the patients from their primary disease, but also to allow the long-term survivor to obtain a normal health status, to return to work or to school and to have a normal social life. Immediate survival is therefore no longer the sole concern. Still, HSCT remains associated with considerable morbidity and mortality. Long-term health status and the development of late events related to HSCT have therefore gained increasing interest. Secondary malignant diseases are of particular clinical concern as more patients survive the early phase after transplantation and remain free of their original disease. Nonmalignant late effects are heterogeneous, and although often non-life threatening they significantly impair the quality of life of long-term survivors. This Chapter presents an overview of these malignant and non-malignant late complications, describes the consequences of these late events on the general health status, social integration and quality of life in long-term survivors, and provides recommendations regarding their prevention and early treatment (1, 2). Readers will find extensive literature summary and references in recently published reviews (3 5). 2. Non malignant late complications (Table 1) (2) 2.1. Late ocular effects Ocular complications of the posterior segment These can be divided into microvascular retinopathy, optic disk oedema, haemorrhagic complications and infectious retinitis. Fungal infections typically occur within 120 days of HSCT, while Herpes zoster, CMV and Toxoplasma retinitis occur later. Ischaemic retinopathy with cotton-wool spots and optic-disk oedema has been described in 10% of patients following HSCT. Microvascular retinopathy occurs mainly after TBI conditioned allogeneic HSCT in patients receiving cyclosporin as GvHD prophylaxis. In most cases, the retinal lesions resolve with withdrawal or reduction of immunosuppressive therapy Ocular complications of the anterior segment The two most common late complications affecting the anterior segment are cataract formation and kerato-conjunctivitis sicca syndrome. Posterior subcapsular cataracts have long been recognised in recipients of HSCT as one of most frequent late complications of TBI. After single dose TBI almost all patients develop cataracts within 3 to 4 years and most if not all require surgical repair. Although the probability of developing cataracts after fractionated TBI is HAEMATOPOIETIC STEM CELL TRANSPLANTATION 237

3 EBMT2008_1_21:EBMT :17 Pagina 238 around 30% at 3 years the incidence may be more than 80% 6 to 10 years post HSCT (6, 7). Use of TBI in general and, single fractionations in particular and the use of Table 1: Non-malignant late tissue and organ toxicity in long-term survivors Organ Eye Clinical manifestation Cataracts Risk factors Monitoring Intervention Radiation Steroids Split lamp examination Fractionation of TBI Surgical repair Keratoconjunctivitis Radiation GvHD Schirmer test Treatment of GvHD Topical lubricants Topical steroids Heart Restrictive or dilated cardiomyopathy Arrhythmia Autonomic neuropathy Anthracyclines Mediastinal radiotherapy LVEF 24-hour ECG Treatment of cardiac insufficiency Pace maker Respiratory tract Chronic obstructive lung disease Bronchiolitis obliterans Infection GvHD Smoking Pulmonary function testing Chest radiographic testing if clinically indicated Treatment of infection Immune globulin replacement Treatment of GvHD Restrictive lung disease Radiation Chemotherapy Infection Pulmonary function testing Chest radiographic testing if clinically indicated Fractionation of radiation Lung shielding Treatment of infection Steroids Liver Chronic hepatitis C Liver cirrhosis HVC infection Iron overload HCV infection Iron overload Liver tests Hepatitis serologies Viral load if positive Ferritin Treatment of hepatitis C Treatment of iron overload (phlebotomy or chelation therapy) Chronic GvHD of the liver Kidney Nephropathy TBI Chemotherapy (platinum) Cyclosporin Liver biopsy if indicated Renal function tests Treatment of GvHD Control of hypertension continue 238 THE EBMT HANDBOOK 2008 REVISED EDITION

4 EBMT2008_1_21:EBMT :17 Pagina 239 CHAPTER 12 Late effects Organ Skeletal Clinical manifestation Avascular necrosis of the bone Risk factors Monitoring Intervention Steroids Radiation Radiographic testing Avoidance of long term treatment with steroids Symptomatic relief of pain Orthopoedic measures Surgical repair Osteoporosis Steroids, cyclosporin, tacrolimus Hypogonadism, TBI, chemotherapy Immobility Dual photon densitometry Sex hormone replacement Treatment of osteoporosis (bisphosphonates, calcium, vitamin D) Oral Chronic stomatitis Chronic GvHD Radiation Oral inspection Oral hygiene Treatment of GvHD Thyroid gland Gonadal function Dental late effects Radiation Chronic GvHD Dental inspection Prophylaxis: oral hygiene, instruction for dental care, brushing teeth, application of fluoride Treatment of caries Hypothyroidism Radiation TSH, T4 annually Thyroid hormone replacement Gonadal failure Radiation Chemotherapy Fertility Infertility Radiation Chemotherapy Nervous system Leukoencephalopathy Cranial radiation Intrathecal chemotherapy FSH, LH, testosterone (males), oestradiol (females) FSH, LH, testosterone (males), oestradiol (females) Sperm analysis Evaluation according to symptoms Hormone replacement Sperm banking in males Cryopreservation of sperm fluid before HSCT Peripheral neuropathy Chemotherapy GvHD Vascular compartment Atherosclerosis Cerebrovascular events Cardiovascular events Peripheral vascular events Established cardiovascular risk factors GvHD (?) Radiation (?) Cardiovascular risk factors Correction of cardiovascular risk factors HAEMATOPOIETIC STEM CELL TRANSPLANTATION 239

5 EBMT2008_1_21:EBMT :17 Pagina 240 steroid treatment for longer than 3 months are associated with a significant risk of cataract development. The development of cataracts is also more likely if the TBI is delivered at a high dose rate. Finally, in prospective studies of the incidence of cataracts according to various risk factors, patients who receive cyclophosphamide and TBI (Cy/TBI) have a higher incidence of cataract formation than those treated with busulfan and cyclophosphamide (BuCy). The only treatment for cataract is to surgically remove the opacified lens from the eye to restore transparency of the visual axis. Today, cataract surgery is a low risk procedure and improves visual acuity in 95% of eyes that have no other pathology. Keratoconjunctivitis sicca syndrome is usually part of a more general syndrome with xerostomia, vaginitis and dryness of the skin. All these manifestations are closely related to cgvhd, which may lead in its most extensive forms to a Sjögren like syndrome. The ocular manifestations include reduced tear flow, keratoconjunctivitis sicca, sterile conjunctivitis, corneal epithelial defects, and corneal ulceration. The incidence of late-onset keratoconjunctivitis sicca syndrome may reach 20% fifteen years after HSCT, but reaches nearly 40% in patient with cgvhd, compared to less 10% in those without GvHD. Risk factors for late-onset keratoconjunctivitis include cgvhd, female sex, age >20 years at HSCT, single dose TBI, and the use of methotrexate for GvHD prophylaxis. Treatment is based on the management of cgvhd with regular use of topical lubricants. Topical corticosteroids may improve symptoms but can cause sight-threatening complications if used inappropriately in Herpes simplex virus or bacterial keratitis Pulmonary late effects Restrictive lung disease Restrictive lung disease is frequently observed 3 to 6 months after HSCT in patients conditioned with TBI and/or receiving an allogeneic HSCT but in most cases it is not symptomatic. Restrictive disease is often stable and may recover, partially or completely, within 2 years. However, some patients do develop severe late restrictive defects and may eventually die from respiratory failure Chronic obstructive lung disease Chronic obstructive pulmonary disease can be detected in up to 20% of long-term survivors after HSCT. It has been mainly associated with cgvhd, but other potential risk factors including TBI, hypogammaglobulinemia, GvHD prophylaxis with methotrexate, and infections have been described. Mortality is high among these patients, particularly in those with an earlier onset and rapid decline of FEV1. Symptoms consist of nonproductive cough, wheezing and dyspnoea; chest radiography 240 THE EBMT HANDBOOK 2008 REVISED EDITION

6 EBMT2008_1_21:EBMT :17 Pagina 241 CHAPTER 12 Late effects is normal in most cases. High-resolution CT scanning may reveal non-specific abnormalities. Symptomatic relief can be obtained in some patients with bronchodilators; however in most cases obstructive abnormalities are not improved by this treatment. Patients with low IgG and IgA levels should receive immunoglobulins to prevent infections, which may further damage the airways. Immunosuppressive therapy may be of benefit but typically improvements occur in less than 50% of cases. Asymptomatic patients with abnormal pulmonary function tests (PFTs) should be closely monitored for the development of respiratory symptoms; an early recognition of airflow obstruction allows the initiation of treatment at a potentially reversible stage. Obliterative bronchiolitis (OB), the best characterised obstructive syndrome, has been reported in 2 to 14% of allogeneic HSCT recipients and carries a mortality rate of 50%. OB is strongly associated with cgvhd and low levels of immunoglobulins. Initial symptoms often resemble those of recurrent upper respiratory tract infections, and then persistent cough, wheezing, inspiratory rales and dyspnoea appear. PFTs gradually deteriorate with severe and non-reversible obstructive abnormalities. Chest radiographs and CT scanning may reveal hyperinflation with or without infiltrates and vascular attenuation; however radiological findings do not correlate with lung function changes. Bronchoscopy with transbronchial biopsy can help to rule out infection and may reveal obliteration of bronchioles with granulation tissue, mononuclear cell infiltration or fibrosis. It is not clear to what extent combined immunosuppressive treatment can be effective in the treatment of this disease, which typically does not respond to treatment with steroids. Azathioprine and mycophenolate mofetil may lead to improved symptoms in some cases. Prophylaxis and prompt treatment of infections are the most important elements of clinical management and may help to alter the clinical course of the disease Late complications of bones and joints Avascular necrosis of bone (AVN) The incidence of AVN varies from 4% to more than 10%. The mean time from transplant to AVN is 18 months and the first clinical manifestation is usually pain. Early diagnosis can rarely be made using standard radiography alone and magnetic resonance imaging is the investigation of choice. The hip is the affected site in over 80% of cases with bilateral involvement occurring in more than 60% cases. Other sites include the knee (10% of patients with AVN), the wrist and the ankle. Symptomatic relief of pain and orthopoedic measures to decrease the pressure on the affected joints are of value, but most adult patients with advanced damage will require surgery. The probability of total hip replacement following a diagnosis of HAEMATOPOIETIC STEM CELL TRANSPLANTATION 241

7 EBMT2008_1_21:EBMT :17 Pagina 242 AVN is approximately 80% at 5 years. While short-term results of joint surgery are excellent in the majority (>85%) of cases, it is clear that long term follow-up of the prostheses are needed in young patients who have a long life expectancy. Studies evaluating risk factors for AVN have clearly identified the use of steroids (both total dose and duration) as the strongest risk factor. Thus, unnecessary long-term low dose steroids for non-active chronic GvHD should be avoided. The second major risk factor for AVN is TBI, the highest risks being associated with receipt of single doses of 10 Gy or higher or >12 Gray in fractionated doses Osteoporosis (8) The degree of reduction in bone mass can be quantified on dual photon densitometry. The cumulative dose and number of days of glucocorticoid therapy and the number of days of cyclosporine or tacrolimus therapy showed significant associations with loss of bone mass. Non-traumatic fractures may occur in 10% of patients. Using WHO criteria, nearly 50% of the patients have low bone density, a third have osteopenia and roughly 10% have osteoporosis, months post transplant. Preventative measures of osteoporosis must include sex-hormone replacement in patients with gonadal failure; the efficacy of new treatments for osteoporosis in long-term survivors of HSCT requires further evaluation Endocrine function after HSCT Thyroid dysfunction Seven to 15.5% of patients will develop sub-clinical hypothyroidism (slightly-high serum TSH and normal free-t4 levels) in the first year post HSCT. It is not yet clear if patients who develop sub-clinical hypothyroidism should be treated with L- thyroxine since the majority of these cases are mild, compensated and may resolve spontaneously. One possible approach is to monitor TSH and free-t4 levels twice yearly and to consider L-thyroxine treatment only if the TSH concentration remains high or is increasing. The frequency of hypothyroidism requiring L-thyroxine replacement therapy is highly variable depending to a large extent on the type of pre-transplant conditioning applied: nearly 90% in patients who have received 10 Gy single-dose TBI, 14 15% of patients following fractionated TBI, and smaller numbers after conditioning with BuCy. Treatment with L-thyroxine is indicated in all cases of frank hypothyroidism (elevated TSH with low free-t4 blood levels). Thyroid hormone levels should be measured 4 6 weeks after commencement of replacement therapy, and dosage should be tailored thereafter to the individual patient and adjusted according to thyroid function evaluation every 6 months. Elderly patients 242 THE EBMT HANDBOOK 2008 REVISED EDITION

8 EBMT2008_1_21:EBMT :17 Pagina 243 CHAPTER 12 Late effects should have an ECG prior to commencing treatment to exclude associated ischaemic heart disease and/or arrhythmias. Autoimmune thyroiditis, presumably transferred via donor cells, has also been reported Gonadal failure Gonadal failure (both testicular and ovarian) is a common long-term consequence of the chemotherapy given prior to HSCT, and of the pre-transplant conditioning. The major cause of gonadal damage leading to hypergonadotrophic-hypogonadism is irradiation. Similar damage can also be caused by busulfan. In males, the testicular germinal epithelium (Sertoli-cells), the site of spermatogenesis, is more vulnerable to radiation and chemotherapy than the testicular Leydig-cell component, which is involved testosterone secretion. Therefore, testosterone levels are usually normal even where spermatogenesis is reduced or absent. The serum FSH is typically elevated while LH levels may remain in the normal range. The great majority of patients will not, therefore, require testosterone replacement to ensure sexual activity, libido, erection and ejaculation. Sex-hormone replacement therapy (SHRT) with testosterone derivatives in males is indicated in patients with severe uncompensated hypogonadism. In females, hypergonadotrophic-hypogonadism is almost inevitable as the ovaries are more vulnerable to irradiation and chemotherapy than the testes. Busulfan is one of the most gonadotoxic agents while cyclophosphamide is usually associated with only minor effects on gonadal function. The majority of adult females will need SHRT in order to maintain menstruation and bone turnover/mineralisation. In prepubertal girls who do not undergo puberty spontaneously post-hsct, oestrogen treatment should be started at the age of years to promote breast and uterine development and the pubertal growth spurt. The dose of oestrogen treatment will need to be gradually increased and a combination of cyclical oestro-progesterone treatment introduced after 1 2 years to initiate menstruation and to reduce the risk of future osteoporosis. SHRT can be interrupted once every 2 3 years, for a period of six months, to evaluate possible spontaneous recovery of ovarian activity, which occurs in the minority of women. Due to the high incidence of gonadal dysfunction and early menopause in patients after HSCT, an annual clinical and biological gynaecological assessment is recommended Special considerations in puberty Hypogonadism occurs in up to 70% of paediatric patients after HSCT. Male patients are more likely than females to enter and progress through puberty. During spontaneous puberty, measurement of testosterone is recommended if the pubertal growth spurt is blunted. A high percentage of female patients will need SHRT. The HAEMATOPOIETIC STEM CELL TRANSPLANTATION 243

9 EBMT2008_1_21:EBMT :17 Pagina 244 probability of ovarian recovery after fractionated TBI is higher in younger patients but after busulfan hypogonadism prevails. Baseline measurements of LH and FSH are recommended at 8 yrs in females and 9 yrs in males. The timing and progression of puberty have a major influence on growth and final height. This must be considered when initiating replacement therapy. Delaying puberty beyond the ages of 13 and 14 yrs is usually not advisable. Temporary cessation of replacement therapy after completion of puberty and growth should be considered in order to evaluate spontaneous recovery. Precocious puberty occurs in a few cases and necessitates gonadotrophin releasing hormone (GnRH)-agonist treatment. Central/hypogonadotrophic hypogonadism can be diagnosed by a GnRH test Fertility following stem cell transplantation The overall incidence of pregnancy is low (<2%) except in patients transplanted for SAA. However, not all patients wish to become parents after HSCT. Some have completed their family prior to transplantation, the proportion of long-term survivors living with a fixed partner is significantly lower compared with siblings and finally, the diagnosis of a potentially life threatening illness makes patients and their partners reluctant to parent children (9). Fertility following HSCT for non-malignant disease Return of gonadal function following cyclophosphamide conditioning without TBI for SAA is reported in half of adult female survivors and roughly 25% subsequently conceived. In adult male survivors 60% have return of sperm production and a quarter subsequently fathered children. Gonadal recovery is usual in women less than 25 years at the time of transplant but sharply decreases thereafter. In thalassaemia, gonadal failure is common as a result of both transfusional hemosiderosis and conditioning with BuCy and pregnancies are very rare. Fertility following HSCT for malignant disease The majority of patients given TBI conditioning experience gonadal failure. Recovery of gonadal function occurs in 10% of the women and the incidence of pregnancy is less than 3% (9, 10). In men, recovery of gonadal function has been reported in less than 20% patients and use of increasing doses of TBI may be associated with considerably lower recovery. Parenting a child following administration of TBI is a rare event in men. However, with increasing follow-up, the impact of TBI on gonadal damage after allogeneic transplantation becomes more attenuated. In a recent study on male fertility, younger age at transplantation, a longer interval between HSCT and the seminal fluid analysis and the absence of cgvhd were associated with a higher incidence of spermatogenesis production (11). BuCy is also associated with a high incidence of gonadal failure in women and there have been no pregnancies reported using BuCy for patients with leukaemia. In men, this 244 THE EBMT HANDBOOK 2008 REVISED EDITION

10 EBMT2008_1_21:EBMT :17 Pagina 245 CHAPTER 12 Late effects preparative regimen appears to be associated with return of gonadal function in approximately 15% cases. Few patients have subsequently fathered children naturally; 20 such patients were identified by the EBMT Late Effects Working Party (LEWP). Fewer studies have evaluated gonadal function following autologous HSCT and most of these have involved small numbers of patients. The use of BEAM conditioning for autografts may be associated with a high incidence of gonadal recovery in women but in men azoospermia is almost always the rule Pre-transplant counselling and treatment options The pre-transplant counselling process should include information about the chance of gonadal failure and should assess the relevance of this to the patient. This should include discussion of assisted conception techniques and in women management of a premature menopause. In women with no residual ovarian function following HSCT, implantation of embryos cryopreserved prior to HSCT is currently the only option for parenting her own genetic child. This, however, requires that prior to HSCT the underlying disease can tolerate a minimum of 4 6 weeks delay in treatment so as to undertake controlled stimulation of the ovary and egg collection. A sperm donor must also be available. In situations where treatment cannot be delayed or there is no sperm donor, consideration can be given to freezing ovarian tissue prior to HSCT. Centres in some countries will provide this service for young women. However the patients must be aware that currently this is a research rather than a clinical option as to date there have been no successful pregnancies in human subjects using this methodology. Sperm cryopreserved prior to HSCT may be used post HSCT for artificial insemination, in vitro fertilisation and embryo transfer or for in vitro injection into the cytoplasm of the oocyte. Post-transplant management should routinely include symptomatic and biochemical monitoring of gonadal function. Distressing vasomotor symptoms may commence acutely post HSCT but this may be prevented by initiating SHRT. While the patient should be prepared for infertility a possible need for contraception soon after HSCT must also be emphasised, particularly in women who resume menstruation or in patients who do not wish to become parents. Patients have conceived within 6 months of HSCT and unexpected pregnancy may result in requests for termination Growth With respect to failure of growth after HSCT, it has been difficult to separate the adverse contributions of the numerous contributory factors. Chemotherapy has an additive negative effect when combined with RT. In general, chemotherapy with Bu/Cy alone does not seem to cause growth impairment but there have been reports of growth hormone deficiency (GHD) after such a combination. In contrast, patients HAEMATOPOIETIC STEM CELL TRANSPLANTATION 245

11 EBMT2008_1_21:EBMT :17 Pagina 246 with neuroblastoma generally do not reach their target height. Cranial (CI), craniospinal (CSI) and TBI can result in growth failure. Single dose TBI (7 8 Gy) causes a loss in final height of 2.0 SD (standard deviations) for boys and 1.0 SD for girls. Much of this loss occurs during puberty. Fractionated TBI (12 Gy) does not cause substantial loss of height with final heights being above 2.0 SD. However, these data were derived from patients who were a median of 10.8 yrs old at the time of transplant, whereas in children younger than 6 yrs the final height was markedly reduced at 3.5 SD. CI prior to HSCT and TBI aggravates the negative effect of TBI. Growth is also disproportionate, with a reduced growth of the spine, which is most severe in CSI. The incidence of GHD following TBI and high dose Cy occurs in 20 70% of children. The diagnosis of GHD may be difficult to establish and repetitive testing may be necessary, as the GH response to stimuli may be discordant. Data on spontaneous GH secretion are scarce. IGF-1 (insulin growth factor 1) and IGF BP-3 (IGF binding protein 3) are unreliable markers for GHD. GH replacement may be started 2 yrs after HSCT on an individual basis. 3. Malignant late complications 3.1. Introduction It has been usual to divide the problem of secondary malignancies following haematopoietic stem cell transplantation into three groups, i.e. leukaemia, lymphoma and solid tumours. The occurrence of second malignancies after HSCT has been extensively reviewed, in particular the critical problem of myelodyplastic syndrome (MDS) and acute leukaemia following autologous HSCT, and rare occurrence of leukaemia in donor cells after allogeneic HSCT (not reviewed in this Chapter; (see ref. 3 and 12 for additional reading and references). The main risk factors are summarised in Table Post-transplant lymphoproliferative disorders (PTLD) (13) Most cases of lymphoproliferative disorders after HSCT have been observed in allogeneic transplant recipients. B-cell PTLD are clinically and morphologically heterogeneous, and are usually associated with T-cell dysfunction and the presence of EBV. The mean interval from transplantation to the development of B-cell PTLD is between 5 to 6 months. In the largest series involving 18,014 patients who underwent allogeneic bone marrow transplantation at 235 centres worldwide, PTLD developed in 78 recipients with 64 cases occurring less than a year after transplantation (9). The cumulative incidence of PTLD was 1.0±0.3% at 10 years. The incidence was highest 1 5 months post-transplant (120 cases/10,000/year) 246 THE EBMT HANDBOOK 2008 REVISED EDITION

12 EBMT2008_1_21:EBMT :17 Pagina 247 CHAPTER 12 Late effects followed by a steep decline to less than 5/10,000/yr among 1 year-plus survivors. B-cell PTLD are almost always of donor origin, and are associated with EBV-genomic DNA integration. Biopsies reveal monomorphic or polymorphic, diffuse large-cell lymphoma of B-cell origin. The most frequent presenting features of PTLD are fever, with or without nodal and extra-haematopoietic organ involvement. Today, the availability of quantitative polymerase chain reaction (PCR) for EBV DNA has dramatically changed the ability to make an early and accurate diagnosis. Using EBV viral load, patients are now frequently diagnosed with PTLD at the time of isolated fever with (or even without) low tumour burden and a monoclonal gamma-globulin. Quantitative PCR techniques allow frequent monitoring of the DNA load to predict the development of PTLD. The presence of EBV-specific T-lymphocytes can also be monitored using tetramer technology, which allows detection of minute numbers of antigen-specific T-cells. The risk of early-onset PTLD (less than a 1 year) is strongly associated with unrelated or HLA mismatched related donors, T-cell depletion of donor marrow or use of anti-thymocyte globulin for prophylaxis or treatment of agvhd. Methods of T-cell depletion that selectively target T-cells or T+NK cells are associated with markedly higher risks of PTLD than methods that removed both T and B-cells, such as the Campath-1 monoclonal antibody or elutriation. Most recently the efficacy of anti-cd20 monoclonal antibody (rituximab) in the treatment of PTLD after HSCT has been reported. Currently many groups consider pre-emptive treatment based on increased EBV load in high-risk patients. Whether this approach is safe and efficacious requires further longitudinal multi-centre studies. The use of cellular therapy has also been advocated in this setting. However, it may induce GvHD if non-ebv-specific CTL are used and still requires high-level biotechnology laboratories to provide either EBV-specific CTL clones or T-lymphocytes transduced with suicide genes that can be activated in the event of any harmful effects Solid tumours The median elapsed time from HSCT to the presentation with a solid tumour is between 5 to 6 years. The cumulative incidence of invasive solid cancers is in the order of 8% at 20 years. The risk increases with time since transplantation with no evidence of a plateau. In a collaborative study, Curtis et al. (14) analysed the results from 19,220 patients transplanted between 1964 and There were 80 solid tumours giving an observed/expected ratio of 2.7. In patients surviving at least 10 years after transplantation, the risk was increased 8 fold. The risk was increased significantly for melanoma, cancers of the buccal cavity, liver, CNS, thyroid, bone, HAEMATOPOIETIC STEM CELL TRANSPLANTATION 247

13 EBMT2008_1_21:EBMT :17 Pagina 248 and connective tissue. The risk was highest for the youngest patients and declined with age. Most striking was the link of squamous cell carcinoma with cgvhd and male gender. The underlying diagnosis was important in so far as the risk of solid tumours was higher for patients with leukaemia and lower in patients with lymphoma or aplastic anaemia. The risk associated with TBI declined if irradiation was given with a fractionation regimen but increased with the total cumulative dose. This analysis strongly suggests that reduced doses of TBI, the omission of limited field irradiation, and the prevention of GvHD, in particular cgvhd, should reduce the risk of post-transplant solid tumours. The main features of solid tumours occurring after HSCT include: - The incidence of the second malignancy continues to increase with prolonged follow-up without any evidence of a plateau - Irradiation is the strongest risk factor but recent data suggest that solid cancers can also occur after non-irradiation based conditioning regimens - Chronic GvHD and/or its treatment is strongly associated with the occurrence of squamous cell carcinoma - Studies to try to identify cancer-specific risk factors are on-going (see Table 2) - Biological data are required to investigate the oncogenic process in recipients of HSCT - Most patients who have undergone allogeneic HSCT had already received substantial amounts of chemotherapy and radiation before transplant. The role of those pre-transplant treatments on the occurrence of solid tumours clearly needs evaluation. The treatment of patients with second solid tumours is unclear. There are few data to answer this critical and practical question. Patients with SCC of the head and neck Table 2: Risk factors for second malignancies according to tumour type Risk factor TBI Limited field irradiation T-cell depletion Chronic GvHD HLA-mismatch ATG, OKT3 Acute GvHD Oncogenic viruses Second malignancies Melanoma, thyroid, CNS tumour SCC, head and neck Melanoma, PTLD SCC, head and neck, skin PTLD PTLD PTLD PTLD, SCC head and neck 248 THE EBMT HANDBOOK 2008 REVISED EDITION

14 EBMT2008_1_21:EBMT :17 Pagina 249 CHAPTER 12 Late effects have a bad prognosis using conventional therapy with surgery and/or radiotherapy. With this exception patients with solid tumours can generally be treated safely with conventional treatment. 4. Health status, social integration and quality of life after HSCT Patients who survive more than 5 years after HSCT are generally in good health and are socially reintegrated (15). Most of them regain normal or minimally impaired clinical performance and full social activity in work and school. The clinical performance status of more than 90% of patients is compatible with normal activity (Karnofsky scores of 90 to 100%). More than 90% of patients return to full-time work or school. However, the risks for illness and death are increased in long-term survivors. Patients who survive disease-free for 2 years after allogeneic HSCT have a 10-fold increased risk of mortality compared with an age-matched general population. The mortality continues to be significantly increased even for those who have survived 15 years after transplantation. The major causes of death are late recurrence of the original malignant disease, cgvhd, late infections without GvHD, secondary malignancies, pulmonary complications and cardiac complications. Despite the fact that functional well-being is good, there are still considerable differences compared to their sibling donors. As compared with sibling donors, fewer long-term survivors are currently married, and they have more difficulty holding jobs and obtaining health/life insurance (16). Quality of life (QoL) refers to every dimension of life except for its length, and includes physical abilities, symptoms, social well-being, psycho-emotional status, and spiritual/existential qualities. It reflects how well people feel, what they can accomplish, how satisfied they are with their lives, and whether their lives have meaning and purpose. Following HSCT, QoL can range from perfect, with no physical, emotional or social sequelae and a greater appreciation for life, to severely compromised with physical disability, pain and psychological despair. However, although long-term survivors report many specific symptoms and limitations in their daily activities, almost all patients indicate they would undergo the procedure again given similar circumstances. Fatigue and sleep disturbances are the most common complains for recipients of both, autologous and allogeneic grafts. Many survivors continue to experience the negative effects of the cancer diagnosis and its treatment on their daily lives, resulting in decreases in their QoL well beyond the completion of therapy. However, positive coping strategies and enhanced quality of life in long-term survivors of cancer have been described. Positive psychological effects of the cancer and its treatment include feelings of being grateful and fortunate to be alive, an enhanced appreciation of life, and increased self-esteem HAEMATOPOIETIC STEM CELL TRANSPLANTATION 249

15 EBMT2008_1_21:EBMT :17 Pagina 250 and sense of mastery. Documented negative psychosocial effects include concerns about the future, heightened sense of vulnerability (my body has let me down), a sense of loss for what might have been (e.g., loss of fertility) and increased health worries or hypervigilance. Large HSCT survivor studies conclude that less than half of survivors report normal functional status in most domains. Many specific physical symptoms and limitations persist, particularly for recipients of allogeneic transplant. Continued improvement over time with re-adaptation and return to some form of normalcy has been observed. Within the 3 first years of HSCT the quality of life is significantly worse compared to the general population, while those surviving in excess of 3 years form transplant claim improvements particularly in social functioning, mental health and vitality (17). However, many long-term survivors still have residual deficits, and approximately 5% of very long-term survivors rate their health as poor. Long-term HSCT survivors report poorer physical, psychological and social functioning, but conversely, more psychological and interpersonal growth, differences that appeared to persist years after transplantation (18). In a prospective, longitudinal cohort study, function was assessed from immediately post transplantation to 5-years later. Physical recovery occurred earlier than either psychological well-being or return to work. The proportion without limitations increased over time. Patients with cgvhd, with less social support before transplantation and women were more depressed after HSCT. Full recovery was a process demanding 3 to 5 years. It is possible that this might be accelerated by effective interventions. At a minimum, screening for depression is recommended. Clinical assessment for psychological symptoms should be maintained annually, with mental health professional counselling for those with recognised deficits. Attention should also be given to the partners of patients, who often report loneliness and to the children, who may suffer from separation from one of the parents. 5. Conclusions Individuals undergoing allogeneic HSCT, even when cured, will never become nonpatients. Allogeneic HSCT is a lifelong commitment for all the patient, his or her family, the primary care physician, the transplantation team, and the healthcare providers and structures have to be created to assure long-term follow-up of survivors after HSCT. References 1. Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: Joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood 250 THE EBMT HANDBOOK 2008 REVISED EDITION

16 EBMT2008_1_21:EBMT :17 Pagina 251 CHAPTER 12 Late effects and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 2006; 37: Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: Joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol. Blood Marrow Transplant 2006; 12: Ades L, Guardiola P, Socié G. Second malignancies after allogeneic hematopoietic stem cell transplantation: New insight and current problems. Blood Rev 2002; 16: Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003; 101: Tichelli A, Socié G. Considerations for adult cancer survivors. Hematology (Am. Soc. Hematol. Educ. Program.) 2005; 22: Benyunes MC, Sullivan KM, Deeg HJ, et al. Cataracts after bone marrow transplantation: Long-term follow-up of adults treated with fractionated total body irradiation. Int J Radiat Oncol Biol Phys 1995; 32 : Tichelli A, Gratwohl A, Egger T, et al. Cataract formation after bone marrow transplantation. Ann Intern Med 1993; 119: Schimmer AD, Minden MD, Keating A. Osteoporosis after blood and marrow transplantation: clinical aspects. Biol Blood Marrow Transplant 2000; 6: Salooja N, Szydlo RM, Socié G, et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: A retrospective survey. Lancet 2001; 358: Sanders JE, Hawley J, Levy W, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87: Rovo A, Tichelli A, Passweg JR, et al. Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD. Blood 2006; 108: Deeg HJ, Socié G. Malignancies after hematopoietic stem cell transplantation: Many questions, some answers. Blood 1998; 91: Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: A multi-institutional study. Blood 1999; 94: Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997; 336: Duell T, Van Lint MT, Ljungman P, et al. Health and functional status of long-term survivors of bone marrow transplantation. EBMT Working Party on Late Effects and EULEP Study Group on Late Effects. European Group for Blood and Marrow Transplantation. Ann Intern Med 1997; 126: Bhatia S, Francisco L, Carter A, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: Report from the Bone Marrow Transplant Survivor Study. Blood 2007; 110: Sutherland HJ, Fyles GM, Adams G, et al. Quality of life following bone marrow transplantation: A comparison of patient reports with population norms. Bone Marrow HAEMATOPOIETIC STEM CELL TRANSPLANTATION 251

17 EBMT2008_1_21:EBMT :17 Pagina 252 Transplant 1997; 19: Andrykowski MA, Bishop MM, Hahn EA, et al. Long-term health-related quality of life, growth, and spiritual well-being after hematopoietic stem-cell transplantation. J Clin Oncol 2005; 23: Multiple Choice Questionnaire To find the correct answer, go to 1. Many late effects in allogeneic haematopoietic stem cell transplantation are related to chronic GvHD. One of the late effects below is clearly unrelated to GvHD: a) Chronic obstructive lung disease b) Cataract formation c) Male infertility d) Squamous cell carcinoma Total body irradiation (TBI) is not directly involved in: a) Secondary tumours after HSCT b) Gonadal insufficiency c) Osteoporosis d) Thyroid dysfunction Which of the following response concerning lymphoproliferative disorders (PTLD) after HSCT is not correct? a) Appear usually within the first 6 months after transplantation b) Risk factors for PTLD are mismatched unrelated donors, T-cell depletion or ATG prophylaxis for GvHD c) Can be treated with anti-cd20 monoclonal antibody (rituximab) d) B-cell PTLD are almost always of recipient origin In long-term survivors after allogeneic HSCT, which of the following statements is true? a) Hypothyroidism is seen in nearly 90% of patients conditioned with BuCy THE EBMT HANDBOOK 2008 REVISED EDITION

18 EBMT2008_1_21:EBMT :17 Pagina 253 CHAPTER 12 Late effects b) The major risk factor for avascular necrosis of bone is TBI, mainly when applied as single dose of 10 Gy or higher c) Younger age at HSCT, a longer interval between HSCT and seminal fluid analysis and the absence of chronic GvHD are associated with a higher recovery of spermatogenesis d) Chronic obstructive pulmonary disease is mainly associated with chronic GvHD and can be efficiently treated with bronchodilatators Which sentence concerning general health status, social integration or quality of life is correct? a) 15 years after allogeneic HSCT the risk of late mortality is no longer increased when compared to a general population b) 75% of patients who survive more than 5 years after HSCT return to full work or school after allogeneic HSCT c) Fatigue and sleep disturbances are the most common complains after autologous and allogeneic HSCT d) Psychological well-being occurs earlier than physical recovery in long-term survivors after allogeneic HSCT HAEMATOPOIETIC STEM CELL TRANSPLANTATION 253