¿VALUTAZIONE PROSPETTICA, IN PAZIENTI SOTTOPOSTI A TRAPIANTO DI CELLULE STAMINALI EMOPOIETICHE, DEL PROFILO DI ADIPOCHINE E DI PARAMETRI CLINICI E BIOCHIMICI LEGATI ALLO SVILUPPO DI SINDROME METABOLICA¿

Background. The term metabolic syndrome (MS) identifies a cluster of cardiovascular risk factors having insulin resistance as a key pathogenetic clue. A high prevalence of a MS-like pattern has been reported in cancer chemotherapy survivors, notably among patients affected by oncohematologic diseases. However, MS in cancer patients clinically differs from its “spontaneous” counterpart, bearing a resemblance to other MS-like pictures observed in solid transplant recipients and in HIV survivors, attributed to immunosuppressive and anti-retroviral drugs. These observations enabled to coin the term “secondary MS” characterized by possible pathogenetic differences with spontaneous MS. Disturbances in adipokine homeostasis have been sometimes claimed as possible alternative pathogenetic clues for “secondary MS”. Hematopoietic stem cell transplantation (HSCT) is a particularly interesting field of investigation, due to the delivery of high dose chemotherapy in autologous and of immunosuppression combined with chemotherapy in allogeneic HSCT. Over the last 15 years, an increased prevalence of MS has been recognized in HSCT recipients as a post-transplant long term effect. Nevertheless, most of the available study have a retrospective design and mainly refer to allogeneic HSCT, overlooking the contribution of high dose chemotherapy alone. Moreover, the inclusion criteria are widely different among the reports and do not consider possible pathogenetic clues. In a previous retrospective study, our group reported an increased prevalence of MS among HSCT long term survivors in continuous CR and off therapy, associated with an altered pattern of adipokine expression. In a subsequent study we proved that post-transplant MS differ from spontaneous MS by distribution of the single MS features and by adipokine profile. Aim of the study The above considerations enabled us to plan a prospective study aimed at evaluate in a series of HSCT recipients, at fixed intervals, the prevalence of MS features and the evolution of biochemical and biological parameters possibly involved in MS pathogenesis. Materials and methods After approval by the local Ethic Commission, patients referred either to autologous or allogeneic HSCT, were enrolled to the study over a two years period. For each patient, an anonymous record including anamnestic and clinical data, laboratory and adipokine profile was made. Data were collected at fixed interval: before transplant, after a month, after 100 days, after a year and subsequently every each year. According to the ATPIII criteria a diagnosis of MS was established and each of its components was defined. At each time, patients with MS were compared with those without. In order to better assess the risk of developing MS, the series was also split into three groups: patient with baseline MS, patients developing MS and patients never developing MS. Baseline values were also compared with those of 27 post-transplant MS patients, 27 healthy controls and 27 patients with spontaneous MS of a subsequent comparative study. The following variables were considered as possibly linked to the development of MS or each of its component: age, sex, baseline disease, type of transplant (autologous or allogeneic), blood glucose, insulin, insulin resistance index (HOMA IR = fasting insulin mcU/mL x fasting glucose mmol/L), HbA1c, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol according to Friedewald formula, uric acid, microalbuminuria, CRP, fibrinogen, TSH, FSH, LH, testosterone, 17-beta estradiol, familiar history for diabetes or cardiovascular diseases, leptin, alpha-TNF, resistin, adiponectin, hypogonadism (testosterone < 231 ng/100 mL in men, 17- -estradiol < 20 pg/mL in women), GVHD and smoking. Relationships between the selected variables and MS or its single features were assessed at each time point with a univariate analysis, through the Student t test for differences in median values and through the chi-square test for differences in incidences, and with a multivariate analysis through a Cox regression model. Results Ninety-nine patients undergoing HSCT (M/F 58/41, autologous 52, allogeneic 47, median age 49 years, range 20-69) were enrolled in the study and had completed a year of follow up. Relying on basal values, a diagnosis of MS could be established 24 patients, 11 referred to autologous and 13 to allogeneic HSCT. Eleven additional patients had double dyslipidemia, 6 referred to autologous and 5 to allogeneic HSCT. Patients with MS had significantly higher leptin (p<0.01) and fibrinogen (p<0.01) and lower adiponectin (p<0.01) levels in comparison with patients without MS. Patients with double dyslipidemia (DD) had significantly higher leptin (p<0.01) and fibrinogen (p<0.05) and lower adiponectin (p<0.01) levels in comparison with patients without DD. Patients referred for HSCT differed from a local reference population because of higher leptin (p<0,01) and lower adiponectin (p<0,05) levels; conversely, their leptin levels were comparable with those of patients with spontaneous MS and lower than those of post-transplant MS. Adiponectin levels were comparable with those of patients with post-transplant MS and significantly higher than those of patients with “spontaneous” MS ( p<0,05). After one month 43 HSCT patients, 13 autologous and 30 allogeneic HSCT patients, had MS. Eight additional patients had isolated double dyslipidemia, 5 after autologous and 3 after allogeneic HSCT. After 100 days, 9 patients had died, 6 of them having MS; a diagnosis of MS could be established in 34 patients. Isolated double dyslipidemia was observed in 9 patients, one autologous and 8 allogeneic HSCT recipients. After one year, 77 patients were still alive and in follow up. Of 16 deceased patients, 12 had MS. A diagnosis of MS could be established in 21 patients, whereas in three additional patients a previous diagnosis of MS could not be more confirmed. Isolated DD was observed in 8 patients, one autologous and 7 allogeneic HSCT recipients. At each interval, leptin levels were significantly reduced and adiponectin levels significantly increased in comparison to basal values. Nevertheless, patients with MS still retained a significantly altered adipokine pattern in comparison to those without. The excess in mortality of MS patients in comparison to those without, was statistically significant (p<0.04). At univariate analysis, basal adiponectin, resistin, leptin and fibrinogen levels were risk factors for developing MS. At subsequent times, leptin and resistin still resulted as risk factors for developing MS in the whole series and in autologous HSCT, but not in allogeneic HSCT; similar results were obtained for HOMA and insulin. At the different time intervals, leptin, resistin and HOMA proved to be risk factors more frequently related to the development of the single HSCT features. Moreover, patients with likely reduced previous chemotherapy exposition (multiple myeloma and autoimmune diseases) had a significantly lower risk of developing MS (p<0.02). At multivariate analysis, baseline HOMA (p<0.002), microalbuminuria (p<0.04), leptin (p<0.001) and type of transplant (p<0.002) were significant linked to the presence MS. At +30 days, HOMA (p<0.05), HBA1c (p<0.003) and type of transplant (p<0.03) were significantly linked to the presence of MS. Moreover, the presence of one of the MS features (waist circumference p<0.0001, hypertension <0.01, blood glucose p<0.03 and triglycerides p<0.0001) at baseline evaluation were predictor of developing +30 days MS. Conclusions The study bears no resemblance to the other available due to the prospective design, the inclusion of autologous HSCT patients and the evaluation of insulin resistance and adipokines. The major limitation is the relatively small size of the series. Baseline data show that patient referred to HSCT, are a population with a high prevalence of metabolic syndrome. This finding is in keeping with multiple papers dealing with MS among cancer chemotherapy survivors. Moreover, we confirm our and other previous findings that MS both after cancer chemotherapy and HSCT differ by clinical features because of higher prevalence of dyslipidemia and a lower rate of hypertension, so suggesting a somewhat different pathogenesis. Univariate and multivariate analysis underscore the major role of an altered adipokine profile, notably hyperleptinemia. As in the only comparable retrospective study, we found a burst of MS at +30 day after HSCT. The major determinants were insulin resistance and immunosuppression. The effect of previous chemotherapy cannot be underestimated, since patients with a presumably lower load of previous chemotherapy had a significantly lower risk of developing MS. As suggested by other investigations, double dyslipidemia patients built up a major reservoir of new MS cases. More generally, multivariate analysis reveals that patients with one baseline MS feature had an increased risk of subsequently developing MS. An apparent decrease in MS prevalence at +100 days and at one year, is significantly related to an higher short term mortality among patients developing post-transplant MS. Since both autologous and allogeneic HSCT recipients are involved, both TRM and early relapse are related to MS. The presented data help defining a model encompassing post chemotherapy and post-transplant MS. Cancer chemotherapy patients are a population characterized by an increased prevalence of MS with some particular clinical features pathogenetically related to adipokine profile disturbances. In the early post-transplant, a burst of MS is registered, mainly related to insulin resistance and immunosuppression and mainly deriving from patients with one baseline MS feature but not full blown MS. A medium term decrease in MS is related to an increase in mortality among patients developing post-transplant MS. A subsequent progressive increase in MS rate is attributable to an adipokine profile derangement among long term HSCT survivors, as suggested in our previous retrospective study.