Page 299 - Haematologica May 2020
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Testosterone and post-transplant outcome of men
    In our study, impact of pre-transplant testosterone on outcome was observed only in the subgroup of male patients allografted for AML. Lower levels of pre-trans- plant testosterone were associated with worse OS and PFS post-transplant, largely due to a significantly increased risk of NRM. The reason for this disease-specific association is unclear.
In general, testicular damage and dysfunction, which result in low testosterone status, appear to be rather long- term sequelae of cytotoxic chemotherapy, and the clinical- ly most significant toxicities are observed after regimens employing higher doses of alkylating agents.21 In contrast, adult AML patients considered eligible for alloSCT are usually treated by combination therapy employing anthracyclines and antimetabolites in both first-line and salvage treatment approaches. As patients in advanced disease stage are likely to have received more aggressive therapy prior to transplant and to account for the more deleterious effect of treatment intensity, we have consid- ered disease stage prior to alloSCT as confounding vari- able in all multivariable models. In both cohorts, the asso- ciations of pre-transplant testosterone with worse out- come were not confounded by disease stage prior to trans- plant.
One possible explanation for the observed disease-spe- cific association may be related to the immunoregulatory cytokine network in human AML, including leukemia cell-derived angiopoietins and the interleukin-33/ST2 axis, and the likely cross-talk between leukemic and endothe- lial cells.22-26 Notably, soluble ST2 and angiopoietin-2 were known to be associated with endothelial dysfunction and cardiovascular risk,27,28 and in the context of alloSCT, both were highly correlated with therapy-refractoriness of
A OS since acute GvHD - training cohort
Time since acute GvHD (months)
C PFS since acute GvHD - training cohort
Time since acute GvHD (months)
acute GvHD and high overall mortality.3,29 Given the inverse correlation of pre-transplant serum levels of testos- terone with soluble ST2 observed in our patients, some speculation about endothelial involvement in the present study may appear justified.
Analysis of non-relapse causes of death revealed that pre-transplant testosterone levels tended to be lower in patients that later succumbed to acute GvHD and/or its treatment, and lower pre-transplant testosterone levels were also associated with shorter survival after onset of GvHD. In this regard, our findings fit into the concept of “endothelial vulnerability”.3,4 In the setting of alloSCT, this concept describes a condition/predisposition that mani- fests itself particularly after a severe challenge, such as conditioning therapy or GvHD. Since this “vulnerability” is, at least in part, a characteristic of the recipient’s endothelial cell system, a corresponding increased risk of mortality may already be identified prior to transplanta- tion by assessing endothelial biomarkers. Accordingly, low(er) pre-transplant testosterone, which represents a known determinant of endothelial dysfunction in men,7 may therefore promote and/or enhance this “vulnerabili- ty”, resulting in the observed increase in treatment-related mortality.
However, it should be noted that our study design is not able to definitely support (or refute) the hypothesis of endothelial involvement. Although the associations of lower pre-transplant testosterone levels with worse out- come in the training cohort continued to hold true when additional confounding variables that reflect comorbidi- ties and the patients’ nutritional and overall status were included in the multivariable models, the possibility that lower pre-transplant testosterone is primarily an expres-
 Figure 2. Impact of pre-transplant testosterone status on outcome measures after onset of acute graft-versus-host disease (GvHD) in the training and in the con- firmation cohorts. (A and C) Distribution of overall survival (OS) and progression-free survival (PFS) since onset of acute GvHD in the training cohort. (B and D) Distribution of OS and PFS since onset of acute GvHD in the confirmation cohort. Curves of patients with low (<250 ng/dL) and high (≥250 ng/dL) pre-transplant testosterone status are shown in blue and in red, respectively.
B
OS since acute GvHD - confirmation cohort
Time since acute GvHD (months) PFS since acute GvHD - confirmation cohort
Time since acute GvHD (months)
D
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