Page 302 - Haematologica May 2020

A. Radujkovic et al.
Table 4. Multivariable analysis of the confirmation cohort with the end points overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and relapse following allogeneic stem cell transplantation and OS and PFS after onset of acute graft-versus-host disease (GvHD) (complete case analysis).
OS PFS NRM* Relapse* OS after (n=165) (n=165) (n=165) (n=165) acute GvHD*
PFS after acute GvHD* (n=126)
HR95%CI
Co-variate
Testosterone 1.15 (per 100 ng/dL decrease) (1.03-1.28) Disease stage†
Early Ref Intermediate 1.62
(0.93-2.83) Late 2.48
(1.48-4.15) Age (per 10-year increase) 1.12
P HR95%CI 1.10
0.012 (0.99-1.22)
Ref
1.55 0.088 (0.92-2.62)
2.43
<0.001 (1.48-3.97) 1.09
0.307 (0.89-1.33)
(n=127)
P CHR95%CI P CHR95%CI P HR95%CI P HR95%CI P
1.23 1.02 1.19 1.15
0.062 (1.05-1.43) 0.008 (0.88-1.16) 0.818 (1.05-1.33) 0.004 (1.03-1.28) 0.011
Ref Ref Ref Ref
1.88 1.22 2.01 1.75
0.101 (0.87-4.09) 0.109 (0.61-2.45) 0.579 (1.09-3.74) 0.026 (0.98-3.10 0.057 3.30 1.98 3.21 2.95
<0.001 (1.65-6.62) <0.001 (1.03-3.78) 0.039 (1.78-5.80) <0.001 (1.70-5.12 <0.001 1.32 1.02 1.22 1.16
0.424 (1.03-1.71) 0.031 (0.82-1.26) 0.893 (0.99-1.50) 0.068 (0.96-1.40) 0.127
(0.90-1.37)
Conditioning
Donor
Relateddonor Ref Ref -------- Unrelated Donor 1.22 0.93
(0.65-2.29) 0.528 (0.52-1.65) 0.806
Recipient - donor sex match
Donor source
PB Ref Ref -------- BM 1.29 1.75
(0.49-3.39) 0.605 (0.77-3.97) 0.182
Numberofevents:OS,n=87;PFS,n=97;NRM,n=46;relapse,n=51;OSafteracuteGvHD,n=67;PFSafteracuteGvHD,n=75.*Slimmodel.†AccordingtoGratwohletal.13 BM:bone marrow; CHR: cause-specific hazard ratio; CI: confidence interval; HR: hazard ratio; MAC: myeloablative conditioning; PB: peripheral blood; RIC: reduced intensity conditioning.
MAC Ref Ref -------- RIC 1.81 1.65
(0.88-3.71) 0.10 (0.85-3.21) 0.137
Matched Ref Ref -------- Male recipient / 1.63 1.15
female donor (0.95-2.81) 0.075 (0.68-1.97) 0.604
total testosterone levels were based on a single serum sample. However, it should be noted that single-point measurements of total testosterone and androgens were demonstrated to be a reliable indication of the long-term hormonal status of men.34 Certainly, further prospective, and preferably interventional, studies are needed to con- firm our findings.
As regards intervention, the “optimal” cut-off value for definition of “low testosterone” needs to be discussed. Most studies on cardiovascular health and cardiovascular risk assessment applied values between 100-350 ng/dL (corresponding to 3.5-12.1 nM), as indicated by a recent systematic review.35 In the prospective “T trials”, testos- terone levels <275 ng/dL (approx. 9.5 nM) were used as indications for intervention.31 However, men undergoing alloSCT represent a distinct patient cohort. And although the available evidence indicates that testosterone replace- ment therapy is largely considered to be safe in most men, some controversies remain, and the inherent risk of adverse effects, particularly in selected high-risk popula-
tions, should not be ignored.36 In our study, median pre- transplant testosterone levels in all male cohorts were above the aforementioned range. It should further be noted that, since data on clinical signs of hypogonadism cannot be ascertained retrospectively, patients of the low pre-transplant testosterone group (<250 ng/dL) in our study may not necessary be androgen deficient. In the present study, an optimized cut-off point of 250 ng/dL was derived and was shown to be associated with a 2-fold risk of death post transplant and after onset of acute GvHD in men allografted for AML. This cut-off value of 250 ng/dL is consistent with one definition of “low testos- terone”35 and was shown to be associated with mortality also in non-transplant settings,15,16 and may thus be applied in a pilot clinical trial. Certainly, any future prospective study should also assess clinical signs of androgen defi- ciency, including additional biochemical testing.
In summary, our study suggests that pre-transplant testosterone has an impact on NRM and thus may be a determinant of outcome in male patients allografted for
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