Page 295 - Haematologica May 2020

Testosterone and post-transplant outcome of men
Methods
Results
Discovery cohort
Patients', disease and transplant characteristics of the male patients of the discovery cohort (n=346) are summa- rized in Online Supplementary Table S1. Median follow up of survivors was 65 months (95%CI: 57-73). Median pre- transplant total testosterone serum level was 400 ng/dL [interquartile range (IQR) 269-584].
In univariable analysis, lower pre-transplant testos- terone as continuous variable was significantly associated with shorter OS and PFS (HR for a decrease of 100 ng/dL, 1.11, 95%CI: 1.03-1.20, P=0.005 and HR 1.12, 95%CI: 1.05-1.20, P=0.001, respectively). This was due to a signif- icantly higher risk of both NRM and relapse (CHR 1.15, 95%CI: 1.02-1.28, P=0.018 and CHR 1.11, 95%CI: 1.01- 1.20, P=0.023, respectively). However, in both the “slim” and “full” multivariable models, significant associations of pre-transplant testosterone with any end point could not be confirmed. This was based on a statistically significant interaction between pre-transplant testosterone and the diagnosis AML for the end point NRM (Online Supplementary Table S2).
Accordingly, lower levels of pre-transplant testosterone were significantly associated with shorter OS and PFS, and higher hazard of NRM and relapse only in the sub- group of patients allografted for AML (n=176) but not for other diagnoses (n=170) as revealed by the univariable models (Online Supplementary Table S3). Patients' and transplant characteristics of AML versus non-AML patients are also provided in Online Supplementary Table S1. Consequently, further analyses were restricted to male patients with AML, henceforth referred to as the 'training cohort' (n=176).
Pre-transplant testosterone and post-transplant outcome in the training cohort
Patients', disease and transplant characteristics of the training cohort are summarized in Table 1. Median pre- transplant total testosterone serum level was 423 ng/dL (IQR 256-611; for distribution, see histogram in Online Supplementary Figure S1A) and the estimated median fol- low up of survivors was 36 months (95%CI: 32-47). The cumulative incidence of acute GvHD grade 3-4 on day +100 post-transplant was 5.1% (95%CI: 1.7-8.4). Pre- transplant testosterone had no impact on the hazard of acute GvHD grade 3-4 (HR 0.92 95%CI: 0.74-1.15, P=0.448).
Since testosterone might also reflect the individual’s health and nutritional status prior to alloSCT, pre-trans- plant testosterone levels were correlated to additional patients' characteristics: body-mass index (BMI), levels of C-reactive protein (CRP), performance status and comor- bidities prior to alloSCT. These data were only available for the training cohort and are summarized in Online Supplementary Table S4. Pre-transplant testosterone levels were weakly negatively correlated to pre-transplant CRP levels (Spearman's rho: -0.17, P=0.025) and were not cor- related to the BMI (Spearman's rho: -0.12, P=0.107). However, pre-transplant testosterone levels were lower in obese patients of the training cohort (BMI ≥30 kg/m2, P=0.028) (Online Supplementary Figure S2A). The median pre-transplant testosterone levels were similar between patients with elevated (>5 mg/L) and non-elevated (≤5
Patients
Patients were eligible for this study if they were allografted for a hematologic malignancy between 2002 and 2017 at the University Hospital Heidelberg, Germany, and had serum sam- ples available for measurement of pre-transplant testosterone levels. Pre-transplant testosterone levels were assessed in all male patients meeting these criteria (discovery cohort, n=346). The independent confirmation cohort consisted of male patients diagnosed with AML who had undergone allografting at the University Hospital Essen between 2009 and 2013 and had serum samples available for measurement of testosterone levels (n=168). In addition, pre-transplant testosterone levels were also measured in a small pilot cohort of female patients allografted for AML in Heidelberg (n=32).
Written informed consent for sample and data collection according to the Declaration of Helsinki was obtained for all patients, and the local ethics committees approved the study. Patient data were obtained from medical records and chart review. Disease status prior to alloSCT was assessed applying published criteria.13 Further details regarding transplant proce- dure are provided in the Online Supplementary Appendix.
Assessment of pre-transplant testosterone serum levels
Serum samples were collected between 0 and 2 weeks before alloSCT and cryopreserved at −80°C. Serum levels of total testosterone were assessed retrospectively in the last serum sample before start of the conditioning treatment. The meas- urements were carried out using accredited laboratory meth- ods. A detailed description of the methodology is provided in the Online Supplementary Appendix. Serum concentrations of total testosterone were expressed in ng/dL (for conversion of ng/dL into nM divide by a factor of 28.8). None of the patients had received sex hormone therapy previous to, or at the time of, sample collection.
Statistical analysis
Overall survival (OS), progression-free survival (PFS) (time to relapse or death from any cause), time to relapse, and non- relapse mortality (NRM) (time to death in absence of prior relapse) were calculated from the date of alloSCT to the appro- priate end point. NRM and recurrence of the underlying malig- nancy were considered as competing events. Since acute GvHD and its treatment are major contributors to post-transplant mor- tality, OS, PFS, incidence of NRM and relapse were also assessed after acute GvHD (i.e. in patients who developed acute GvHD, from the date of its onset).
Since the normal physiological range of serum testosterone has not been well defined, pre-transplant testosterone was first analyzed as a continuous variable in the uni- and multivariable models. Cox proportional hazards regression analysis was applied for OS, PFS, and OS and PFS after acute GvHD. Relapse and NRM were analyzed by cause-specific Cox models. Prognostic impact of pre-transplant testosterone on OS, PFS, OS and PFS after acute GvHD was assessed by hazard ratios (HR) and, in case of time to relapse and NRM, by cause-specific haz- ard ratios (CHR) from corresponding (cause-specific) Cox mod- els. Multivariable (cause-specific) Cox regression models were used to adjust for additional co-variates. All statistical tests were two-sided. For further details on the statistical methods used for analysis see the Online Supplementary Appendix.
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