“CARDIOVASCULAR and Metabolic Complications in Patients with Hematological Malignancies Undergoing Allogeneic Hematopoietic STEM CELL Transplantation (HSCT)”

Background: HSCT has greatly improved the prognosis of patients affected by hematological malignancies leading to more long-term survivors. However, long-term survivors are at increased risk of developing complications; cardiovascular complications are relatively rare but, on the other hand, it seems quite common to develop cardiovascular risk factors like: arterial hypertension (AH), diabetes, dyslipidemia.

Aims of the study: to observe the incidence and outcome of patients developing cardiovascular risk factors (CVRF) and cardiovascular events (CVE) after allo-HSCT, eventually identifying patient and HSCT-related risk factors for CVE (CVE predictors).

Materials and methods: We retrospectively analyzed 300 patients undergoing allo-HSCT from January 2006 to December 2009. Patients were considered long-term survivors and suitable for the analysis if they were alive at 2 years after HSCT. Following variables were recorded: diagnosis, sex, age at time of HSCT, comorbidities and pre-existing risk factors, BMI, previous chemotherapy with anthracyclines, donor type, disease status at time of HSCT, conditioning regimens with or without total body irradiation (TBI), onset of acute or chronic graft versus host disease (aGVHD and cGvHD), treatment with high doses corticosteroids after HSCT. We observed incidence and outcome of early (within 2 years) and late (after 2 years) CVRF and CVE in long-term survivors; CVE were divided in non-serious (grade1-2) and serious (grade 3-4) if they required or not hospitalization. Dichothomius variables were compared with Chi-Square test or Fisher's exact test. Continuous variables were compared with Student's T-Test. Median Follow-Up duration was estimated with Kaplan Meier reverse survival method. Multiple linear regression models were built for multivariate analysis of CVE incidence. A two-sided p value <0.05 (<0.02 for multivariate analysis) was considered statistically significant.

Results: 4 of 300 patients died of acute heart failure within 2 years from HSCT. 149 patients were alive at least 2 years after HSCT, and 125 patients (83%) were alive at the time of last follow-up, with a median follow-up of 2384 days (range 722-3098) and a median age of 40 years (range 15-72). Overall crude mortality was 24/ 149 (17%), of whom 16 patients dying of disease recurrence (66%) and 8 patients (34%) dying due to non-relapse causes (Non Relapse Mortality, NRM). Non-serious CVE were observed in 42 patients (28%), whereas serious CVE were reported in 23 cases (15%; 5 acute coronary syndrome, 4 heart failure, 5 cardiac arrythmias, 5 cerebrovascular events, 2 aortic aneurism, 2 pericarditis), with 11 patients experiencing both. Regarding CVRF, post-HSCT AH was observed in 62 patients (42%), dyslipidemia in 124 pts (83%), diabetes in 29 pts (19%). In univariate analysis older age was associated with a higher risk of developing late diabetes (p 0.025), early and late AH (p<0.001), any CVE (p=0.04). cGVHD was associated with a higher risk of early AH (p 0.018), while aGVHD, advanced disease at HSCT and use of high dose of corticosteroids were associated with serious CVE (respectively p=0.039,p=0.025,p=<0.0001). In multivariate analysis, Event Free Survival (EFS) for any CVE was lower in case of older age (p=0.01), acute and chronic GvHD (p=0.010, p=0.006), pre-existing AH (p=0.001) and smoke abuse (p=0.01), reduced intensity conditioning regimens (p=0.03), and high dose corticosteroids treatment (p=0.001). Furthermore, serious CVE were associated with male sex, reduced intensity conditioning regimen, use of TBI within conditioning regimens, older age, and pre-existing AH (respectively p=0.006, p=0.026, p=0.002, p=0.009, p=0.038). Older age was also associated with the development of late AH (p=0.001) and late diabetes (p=0.025)

Conclusions: Older allo-HSCT patients have an higher risk of developing any CVE and any CVRF than age-matched non-hematologic population; interestingly, prolonged treatment with high dose steroids also seems to play a role. CVE do not show nowadays a high impact on survival since they seems to be an uncommon complication of HSCT. Furthermore an increasing number of late CVRF has been observed, possibly leading to late cardiovascular events in the future and should therefore be monitored.