Organ toxicity and quality of life after allogeneic bone marrow transplantation in pediatric patients: a single centre retrospective analysis

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1 Bone Marrow Transplantation, (1999) 23, Stockton Press All rights reserved /99 $ Organ toxicity and quality of life after allogeneic bone marrow transplantation in pediatric patients: a single centre retrospective analysis S Matthes-Martin, M Lamche, R Ladenstein, W Emminger, C Felsberger, R Topf, H Gadner and C Peters St Anna Children s Hospital, Vienna, Austria Summary: One hundred and fifty five pediatric patients underwent allogeneic bone marrow transplantation between 1980 and 1996 in the St Anna Children s Hospital in Vienna with an overall survival of 52.3% (81 patients). Seventythree patients with a minimum observation time of 1 year (1 13 years, median: 4.6) were analyzed retrospectively for chronic GVHD, organ toxicity (WHO score), growth and pubertal development. Chronic GVHD was diagnosed in 20 patients (27.3%), being extensive in 17 cases. Maximum organ toxicity was WHO III in two patients (3%) and WHO II in 11 patients (15%) 1 year after BMT and WHO III in one patient (2%) and WHO II in five patients (11%) 3 years after BMT. Impaired growth and pubertal development were detected in more than 30% 3 years after BMT. As all patients presented with a Karnofsky or Lansky score of more than 80%, they were asked to complete a questionnaire comprising 12 questions concerning physical state of health and psychosocial state of health. Restricted contacts were classified as imposing a severe handicap by six patients (8%), restriction in mobility and normal life activities by three patients (4%) and two patients classified themselves as severely physically handicapped. Most patients (75%) reported no physical or psychical impairment. Keywords: allogeneic bone marrow transplantation; children; late effects; toxicity; quality of life adolescent patients. 4 6 The aim of this single-center study was to evaluate retrospectively late effects and quality of life after allogeneic BMT in children. Patients and methods Our study included 73 survivors after allogeneic BMT with an observation time between 1 and 15 years (median: 5.6 years). Eight patients were lost to follow-up and no recent clinical data were available. The median interval between BMT and the study was 4.6 years (range 1 13 years). Median age at time of the study was 13.2 years ( years). Patient characteristics are listed in Table 1; diagnosis, conditioning regimen, donor type, GVHD prophylaxis and treatment in Table 2. Standard cgvhd prophylaxis was cyclosporine until at least day +180 and patients who had experienced agvhd gr II received cyclosporine for 1 year. All patient files were analyzed retrospectively for the intervals 1 year (n = 73) and 3 years, respectively (n = 48) after BMT. Hepatic, renal, cardiac, intestinal and neurological toxicity was scored using the WHO toxicity score as described elsewhere. 7 Additionally, osteoporosis, necrosis of the femoral head, and hypertension were assessed. As the study was retrospective over a period of 15 years and not all patients had undergone the same endocrinological Table 1 Patient characteristics Allogeneic BMT has become an important therapeutic approach for patients with hematologic malignancies and other diseases and results in long-term disease-free survival of more than 50% of patients depending on the underlying disease and transplantation modalities. 1 3 Thus, late effects of radiation and chemotherapy and quality of life in longterm survivors are of increasing interest, particularly in pediatric patients. Most studies report late effects in adult BMT patients and there are few data available concerning pediatric and Correspondence: Dr S Matthes-Martin, St Anna Kinderspital, Kinderspitalgasse 6, A-1090 Vienna, Austria Received 17 September 1998; accepted 20 December 1998 Total No. patients 73 Sex (M/F) 39/34 Age at BMT: years, range (median) (7.9) Diagnosis ALL, CR1 3 ALL CR2 22 ALL CR3 2 AML, CR1 7 AML, CR2 3 CML/CMML 5 SAA/FA/ -Thalassemia 16 SCID/IE 9 NHL/solid tumors 6 CMML = chronic juvenile chronic myelomonocytic leukaemia; SAA = severe aplastic anemia; FA = Fanconi s anemia; IE = inborn errors; NHL = non-hodgkin lymphoma.

2 1050 Conditioning regimens, stem cell sources and GVHD prophy- Table 2 laxis Conditioning TBI + CY (+ etoposide) 32 BU + CY 11 CY + ATG (+TLI) 16 BU + CY + etoposide 6 Others 6 No conditioning (SCID) 2 Donor matched sibling donor 47 matched family donor 4 1-Ag mm family donor 5 matched unrelated donor 17 Source of stem cell BM 69 PBSC 4 GVHD prophylaxis MTX 20 CSA MTX 51 none 2 screening tests, growth, thyroid abnormalities and pubertal development were assessable in most cases by clinical data only. Growth was evaluated for all patients who had been younger than 14 years at the time of BMT and those with Fanconi s anemia were excluded. Growth retardation was defined as a decrease of more than one percentile level compared to height before transplantation. Pubertal development was evaluated in patients less than 11 years of age at BMT and older than 15 years at the time of the study. Acute and chronic GVHD were graded according to the consensus criteria, as described elsewhere, 8 organ involvement other than skin, ie bronchiolitis, joint contractures, was documented separately. Quality of life was scored by Karnofsky or Lansky scores respectively. 9 On routine follow-up, patients were handed a self-assessment questionnaire concerning quality of life. Patients no longer followed-up were invited to visit the outpatient department to complete the questionnaire. All but eight (most of them being from abroad and more than 5 years from BMT) patients (90%) responded to the invitation, five were not able to come but sent back a detailed medical report and the completed questionnaire. Lack of more detailed tools to assess quality of life which are comprehensive and appropriate for children led us to design a questionnaire focusing on the practical aspects of daily life. The first part consisted of questions concerning frequency of medical consultation in the last 4 months prior to the study, school attendance after transplantation and professional career. The second part consisted of 12 items including physical and psychological aspects. As far as physical aspects are concerned, patients were asked whether they felt restricted in mobility, independence, normal life activities, whether they felt pain, whether they considered themselves to be ill or physically handicapped and whether they had problems with their appearance. Selfestimated psychosocial state of health was evaluated by the following questions: Do you feel anxious, nervous or tense? Do you feel depressed? Do you have concentration or memory problems? Do you feel dissatisfied with your life? Do you feel restricted in social contacts? (Table 2). Patients were asked to score each item between 1 (not true) and 4 (true), imposing a great handicap. When the patient was younger than 12 years, parents were asked to fill out the questionnaire. The items were summarized to compare overall self-estimated quality of life with patient and clinical data (ie 12 = excellent self-estimation, 48 = worst self-estimation). Correlation of organ toxicity and quality of life with source of stem cells, underlying disease, cgvhd and interval between transplantation and time of the study was evaluated by using Fisher exact test and logistic regression for continuous independent variables. Results Between 1980 and 1996, 155 pediatric patients underwent allogeneic BMT with an overall survival of 51%. Causes of death were transplant-associated, n = 41 (26%); chronic GVHD and late infections n = 14 (9%); relapse of the underlying disease n = 11 (7%); and in one case death was caused by a secondary malignancy. One year after BMT 3/73 patients (4.1%) presented with limited and 17/73 patients (23.3%) with extensive cgvhd, only 4/17 with HLA-identical sibling donors. Three years after BMT, cgvhd was detectable in a further three patients (two limited and one extensive). Two of 20 patients progressed from limited to extensive GVHD between 1 and 3 years after BMT and an improvement in cgvhd was observed over the same interval in only five patients despite treatment with cyclosporine, low-dose glucocorticoids and PUVA. The incidence and the severity of cgvhd was higher in patients with a history of severe ( gr II) agvhd. Twelve of 73 surviving patients (16%) had experienced acute GVHD gr II. Seven of 12 (58.3%) of the patients who had experienced severe agvhd developed cgvhd vs 13/61 (21.3%) after mild or no agvhd. Patients with the diagnosis of extensive cgvhd showed marked heterogeneity of organ involvement and severity of organ impairment. In 11/17 patients, the diagnosis of extensive cgvhd was based on skin involvement plus sicca syndrome and/or oral mucosa involvement. However, 7/17 patients with extensive cgvhd presented with severe organ impairment such as bronchiolitis (n = 3) or were severely handicapped by joint contractures (n = 4), all of them with a history of agvhd gr II. As far as WHO toxicity is concerned, hepatotoxicity was the most common finding 1 and 3 years after BMT. One year after BMT 10/73 patients (13.6%) showed hepatotoxicity WHO I (bilirubin mg/dl and/or ALAT U/l), 11/73 patients (15%) WHO II (bilirubin mg/dl and/or ALAT U/l) and 2/73 (2.7%) WHO III (bilirubin 5 10 mg/dl and/or ALAT U/l). Three years after BMT, hepatotoxicity was WHO I in 5/43 patients, WHO II in 5/43 (11%) patients and WHO III in 1/43 (2.3%). Nephrotoxicity WHO I was observed in 8/73 (11%) patients (creatinine mg/dl; BUN mg/dl; pro-

3 Table 3 Quality of life questionnaire 1051 Not true No/slight Handicap Severe handicap handicap Physical state of health Restriction in mobility Restriction in independence Restriction in normal life activities Problems with appearance Pain Physical handicap General feeling of illness Psychosocial state of health Anxieties/nervous disorder/tension Dejection/depression Concentration/memory problems Restrictions of satisfaction with life Restricted contacts teinuria 0 3 g/l) 1 year after BMT and in 3/43 (6.9%) patients 3 years after BMT. In no case major renal impairment could be observed. Seven of 73 patients suffered from renal hypertension 1 year after BMT and all were still receiving immunosuppressive therapy with cyclosporine. All but one reverted to normal after 3 years. We found a correlation between hepatic toxicity WHO I and cgvhd. Hepatic toxicity was found in 9/20 patients (45%) with cgvhd vs 3/53 without cgvhd (5%), P = Concerning renal toxicity, the difference between patients with cgvhd (5/20 patients (25%)) and without cgvhd (3/53 patients (5.6%)) was not significant, P = Source of stem cells (MSD vs alternative donors), underlying disease (malignant vs non-malignant) or age at transplantation had no impact on the incidence of hepatic or renal toxicity. Cardiotoxicity WHO I defined as a shortening of fraction between 26% and 30% was observed in three patients (all with a history of mg/m 2 anthracyclines, two of them after TBI-containing conditioning regimen), but returned to normal within 3 years without any other clinical symptoms. Lung function tests had been performed in 39 children 1 year after BMT, four of them, all with the diagnosis of cgvhd, with an obstructive pattern. Although only one patient fulfilled the criteria of intestinal toxicity WHO I, 10 patients presented with reduced body weight compared to height suggesting disturbed intestinal absorption; all were suffering from cgvhd. One patient with familial hemophagocytic lymphohistiocytosis and initial CNS involvement showed severe residual mental retardation and ataxia due to the underlying disease. Only two patients showed mild neurological impairment (peripheral neuropathy 1 year after BMT, which resolved by the third year). No patient with clinical hypothyroidism was observed. Routine TSH, T3 and T4 levels had been tested in all patients 1 year after BMT. Three/73 (4%) were found to have compensated hypothyroidism with elevated TSH and normal T3, T4 levels. Children less than 11 years of age at BMT and older than 15 years at the time of the study were assessed for pubertal development 3 years after BMT. Six out of 18 female patients (33.3%) showed delayed pubertal development and required estrogen therapy. Growth retardation defined by decrease of more than one percentile level compared to the height before transplantation in patients with diagnoses other than Fanconi s anemia was seen in 13/67 patients (19.4%) after 1 year and in 15/39 (38.4%) after 3 years. There was a marked difference in growth retardation 3 years after transplantation between patients with TBI-containing conditioning regimens and those who had undergone conditioning without TBI: 13/19 (68%) vs 2/24 (8%). Six out of 19 patients with TBIcontaining conditioning regimens had received additional cranial irradiation before BMT. The median age at time of transplantation did not differ significantly (6.4 vs 6.8 years) between the two groups. Osteoporosis was detectable radiologically in 7/53 patients (13%), one of whom had pathological fractures. Necrosis of the femoral head occurred in two patients, both still receiving conservative treatment. The median frequency of medical consultation in the 4 months prior to the study was 1.2 (range 0 8). Only four patients had been hospitalized (duration 4 29 days, median 12) within 3 months prior to the study. All but one patient (with severe neurological impairment) presented with a Karnovsky or Lansky score of more than 80%. Relating to the questionnaire for quality of life, 75% of the patients reported no physical or psychological impairment. The most frequently reported restrictions concerned mobility, normal life activities and problems with physical handicap. Three/73 patients (4%) classified their restriction in mobility and/or normal life activities and independence as imposing a major handicap. Six patients (8.5%) scored their restriction in social contact as imposing a major handicap, all were still receiving immunosuppressive treatment, and four were suffering from extensive cgvhd. Quality of life correlated significantly with the diagnosis of cgvhd (P = ) whereas source of stem cells (MUD vs MSD) (P = 0.08) and underlying disease

4 1052 (malignant vs non-malignant) (P = 0.6) were not significant. Self-estimated quality of life in patients with an interval of more or less than 3 years from BMT, was not significantly better in those patients who had undergone BMT more than 3 years prior to the study (P = 0.29). Two of 58 patients had to change school type after BMT, 15/58 had to repeat the year and 1/48 patients who were of school age at the time of the study was not able to attend school because of extensive chronic GVHD and immunosuppression. Two/15 patients who had already finished their education were not able to work in the expected or desired profession. Discussion Better survival after allogeneic BMT during the last 10 years has provoked an increased interest in late effects and quality of life in survivors. There have been many publications concerning quality of life after BMT in adults giving contradictory results and several reports on late effects concerning single organ systems in pediatric BMT patients but there are very few data concerning overall heath status and quality of life in this patient group. 6,16,17 The aim of this single-center study was to detect major organ toxicity 1 and 3 years after BMT and major restriction in normal life in a large unselected heterogeneous group of pediatric BMT patients. There were no exclusion criteria and 73/81 (90%) survivors participated, which may indicate a high level of acceptance concerning the treatment. Chronic GVHD remains a major complication of non-t cell-depleted allogeneic BMT, occurring in more than 30% despite GVHD prophylaxis In our study, 32.8% suffered from cgvhd, which was extensive in most cases. Patients with gr II agvhd had a significantly higher risk of developing cgvhd. Severe agvhd seems to be an important risk factor, regardless of recipient age. 21 It is of note that in three patients cgvhd was detected only after more than 1 year from BMT. Overall organ toxicity was found to be less than expected, taking into account the fact that more than 64% of the patients were transplanted for malignant diseases which implies a history of repeated chemotherapy. A correlation between renal toxicity and cgvhd has been described. 14 We found a strong correlation between hepatic toxicity and cgvhd. Whether this finding is due to subclinical GVHD or to immunosuppressive treatment remains open. Growth retardation and impaired pubertal development were the most prominent findings, which confirms other published data. 4,5,22 Three years after BMT, deficiency in growth and/or pubertal development was evident in one third of patients. As described by others there was a significant difference between TBI- and busulfan-conditioned patients. 23 No cases of clinical hypothyroidism were observed, and elevated TSH levels after 1 year were detected in three patients only. The incidence of compensated hypothyroidism was much lower than reported in other studies. 24 This might be due to the fact that only half of the patients were treated with TBI and radiation was delivered hyperfractionated in eight single doses. That this study is retrospective places several limitations as far as organ toxicity is concerned. First, it has to be acknowledged that this study was performed only on surviving patients and toxicity and quality of life of dead patients were not assessed. Secondly, it was restricted to the clinical data available which implies that several items were not evaluable for all patients. This restriction also led us to use the WHO toxicity score which is the most commonly used toxicity scoring system in oncology but which was developed to score acute toxicity. The WHO toxicity score is particularly inadequate for chronic intestinal toxicity. There was only one patient with a WHO I intestinal toxicity, but 10 patients presented with diminished body weight compared to height, suggesting chronic malabsorption. As far as the questionnaire of quality of life is concerned our study bears two limitations. First, in this part of the study there was no age-adjusted control group of normal people and for patients of less than 12 years parents were asked to fill out the questionnaire. Secondly, our study was cross-sectional with a variable time interval between BMT and self-assessment. After dividing the patients into two groups with an interval of more or less than 3 years after BMT we failed to find a significantly better self-estimation of quality of life in patients after an interval of more than 3 years. This is contradictory to the findings of Sutherland et al 10 in adults after BMT and might be due to the high incidence of cgvhd, taking into account that self-estimated quality of life correlates with the presence of cgvhd. In our study, the restriction most frequently reported 1 year after BMT concerned impaired social contacts due to immunosuppression. As Prieto et al 11 described, we also found a strong association between self-estimation of quality of life and cgvhd. Neurological sequelae do not seem to play a major role after pediatric allogeneic BMT. In another prospective study on psycho-social effects of allogeneic BMT, the findings indicate an absence of significant neurocognitive impairment during the first year after BMT. 16 It should be emphasized that 75% of the patients reported an excellent quality of life and that patients surviving more than 1 year have few detectable organ impairments despite being heavily pretreated and even after experiencing severe complications until day Prospective and more detailed studies are necessary to determine side-effects in pediatric BMT patients. cgvhd particularly implies a great variety of physical and psychological impairments. A more detailed scoring system to assess cgvhd would be of great help. Toxicity as well as quality of life correlate with the diagnosis of cgvhd, suggesting that prevention and treatment of GVHD remain a major challenge. References 1 Amylon MD, Co JP, Snyder DS et al. Allogeneic bone marrow transplant in pediatric patients with high-risk hematopo-

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