Hematopoetik Kök Hücre Transplantasyonu Yapılmış Çocuk ve Adolesanlarda Uzun Dönem Endokrinolojik Komplikasyonlar
Özet
Today developments in hematopoietic stem cell transplantation (HSCT) enables its use in the treatment of increasing number of diseases with success. GVHD prophylaxis and successful treatment of opportunistic infections prolonged life expectancy of survivors (1-3). The main problem for these "old " patients is the morbidity and mortality of late complications. These long term complications impact long-term quality of life in post transplant patients significantly, more so in children and adolescents considering their life expectancy. Endocrine complications are among the most common late effects in cases who have undergone HSCT (4). In the current study, we aimed to determine long term endocrine complications in children and adolescents who have undergone HSCT for malignant and nonmalignant diseases, who are in complete remission after at least two years post transplantation. The analysis was crosssectional and retrospective, also patient and treatment related risk factors that may have an impact on endocrine functions were investigated. Patients who have undergone HSCT between June 1994 and March 2011 were included in the analysis, and prevalence of short stature, thyroid and gonadal dysfunction as well as disorders of bone mineralization (decrease in bone mineral density) was evaluated. In addition, impact of patient and treatment-related factors on endocrine complications were analayzed. A total of 51 patients (23 female, 28 male) were included and the mean age was 13.4 ± 5.0 during the final analysis. Median duration after HSCT was 4.3 years (2.0 to 15.8), and mean age during HSCT was 8.5 ± 4.5 years (3 months- 16, 5 years) respectively. Primary condition was malignant disease in 25,4 % (all hematologic malignancy), İmmunodeficiency in 11,7 %, and nonmalignant diseases in 62,6%. 15 patients (29.4%) had HSCT for Fanconi aplastic anemia (FAA) and these patients were excluded from the assessment growth disorders. 11 patients (21.5%) received chemotherapy previously for the primary disease. All patients received a chemotherapy (CT) –based conditioning regimen, and only two patients received total body irradiation (TBI) prior to HSCT. CR was myeloablative in 24 (47%) patients and, nonmyeloablative in 25 (49%). Three patients had HSCT twice, two received CR twice and one received a single course of CR. HSC source was syngeneic twin in one patient, all the remaining patients received HSC from HLA compatible relative. Growth was evaluated in 36 patients. 35 of these patients had a mean height standard deviation score (SDS) of -1.10 ± 1.36 prior to HSCT; during the final visit mean height SDS was -0.82 ± 1.45. There was no difference between height SDS before and after HSCT (p = 0.15). At the final assesment 8/36 patients (22.2%) was short (height SDS < -2), respectively. An increased risk of short stature was associated with female sex (odds ratio 8.6, 95% confidence interval 1.0 to 73.4) (p = 0.048). Use of MA CR was higher in the group with short stature in comparison to children with normal stature (p = 0.033). Mean target height SDS was calculated to be -0.38 ± 0.96 in 25 patients which was significantly higher than their mean height SDS (-0.91 ± 1.38) at the final visit (p = 0.024). Nine patients reached their final heights (FAH) and only one patient had as FAH SDS ≤ -2. Mean FAH SDS of six patients, whose target height could be determined, was similar to their mean target height SDS. Eight patients (15.7%) were hypothyroid. Of these, 5 had subclinical an done had overt primary hypothyroidism, while two patients had central hypothyroidism. There was no history of RT in the two patients with central hypothyroidism, and thyroid dysfunction could not be attributed to the HSCT in these patients. Hypothyroidism was diagnosed after a median period of 1.0 year (3 months - 2, 8) post transplantation at a mean age of 10.6 ± 5.0 years (3.6 to 16.6). We could not identify any risk factor for thyroid dysfunction after HSCT. Primary gonadal failure was found in 12 of 43 patients at pubertal age. In addition one patient was consistent with hypogonadotropic hypogonadism. Gonadal failure was found after a median period of 3.0 years post transplantation at a median age of 14.9 years. An age of HSCT ≥ 10 years increased risk of gonadal failure 49.8 fold (95%confidence interval 4.4 to 556.9, p = 0.002), whereas NMA CR reduced the risk (0,068 fold 95%confidence interval 0.006 to 0.7 p = 0.028). Age of primary disease as well as age of HSCT was greated in the group of patients with gonadal failure in comparison to the group of patients with normal gonadal functions (p = 0.018 and p = 0.014 respectively). In the group with normal gonadal function the number of children who were ≤ 10 years or prepubertal at the time of HSCT was higher (p < 0.001, p = 0.032 respectively). In addition, frequency of patients with malignant primary disease as well as a history of MA CR was significantly higher in the group with gonadal failure (p = 0.006, p = 0.033 respectively). Spinal (L1-L4) bone mineral density (BMD) was assesed using dual-energy X-ray absorptiometry (DEXA) in 44 patients, and 13 patients (29.6%) had a low (< -1) BMD Z-score. In nine of them (20.5%) BMD Z-score was between -1 and -2, and in 4 (9.1%) it was below -2. A HSCT age of 10 years or more increased the risk of low BMD 5.9 -fold (95%confidence interval 1.182 to 29.363, p = 0.030), and use of NMA CR decreases it (0,094 fold, 95%confidence interval 0.015 to 0.578, p = 0.011). In addition, a higher frequency of patients with malignant primary disease as well as increased use of MA CR was found among patients with low BMD (p = 0.043, p = 0.012). The current study analyzes post HSCT endocrine problems in the long term in a group of children and adolescents after allogenic HSCT, who were given a CR of CT including alkylating agents in all, without a history of cranial RT, and only rare use of TBI. In the literature it is emphasized that long term endocrine complications after childhood HSCT is mainly associated to exposure to radiation. However endocrine complications are also reported following CR including alkylating agents. Our study showed that CR using CT alone without TBI is not completely safe for late endocrine complications, suggesting RT maynot be the sole risk factor of endocrine dysfunction. Significant findings of the current study are a decreased risk of gonadal failure and low BMD in patients using NMA CR, in addition to the increased frequency of MA CR in patients with short stature, gonadal failure, and low BMD. These findings suggest that besides the uncontrollable patient or primary disease related risk factors, CR and its choice may present the main controllable factor with an impact on endocrine dysfunction. One should emphasize the long term positive impact of NMA CRs on long term endocrine outcome.
