Page 296 - Haematologica May 2020

A. Radujkovic et al.
Table 1. Patients' disease and transplant characteristics of male acute myeloid leukemia (AML) patients of the training and confirmation cohorts.
Training cohort n=176
59 (50-64)
114 (65) 62 (35)
Confirmation cohort n=168
56 (45-63)
132 (80) 34 (20)
P
0.818
0.022
0.003
0.632
0.182
0.078
0.043
Parameter
Age [years] at alloSCT (median, IQR) Disease stage before alloSCTa, n (%)
Early
Intermediate
Late
NA 1 1
74 (42) 32 (18) 69 (39)
78 (47) 45 (27) 44 (26)
Conditioningb, n (%) RIC
MAC
NA 0 2
Stem cell source, n (%)
Peripheral blood
Bone marrow Donor, n (%)
Related
Unrelated
Recipient – donor sex match, n (%)
Matched
Male – female
Pre-transplant testosterone,
ng/dL (median, IQR)
168 (96)
8 (4)
41 (23) 135 (77)
127 (72)
49 (28) 423 (256-611)
158 (94)
10 (6)
29 (17) 139 (83)
135 (80)
33 (20) 469 (309-580)
alloSCT: allogeneic stem cell transplantation; AML: acute myeloid leukemia; CI: confidence interval; IQR: interquartile range; MAC: myeloablative conditioning; NA: not available
or not assessable; RIC: reduced intensity conditioning. aAccording to Gratwohl et al.13
mg/L) CRP levels prior to alloSCT (P=0.127) (Online Supplementary Figure S2B). There was a trend towards lower pre-transplant testosterone levels in patients with lower Karnofsky performance status (KPS ≤80%), where- as testosterone levels were similar between the low hematopoietic cell transplantation-specific comorbidity index14 group (HCT-CI 0), intermediate (HCT-CI 1 to 2), and high risk (HCT-CI 3 or more) HCT-CI groups (Online Supplementary Figure S2C and D; for further details see the Online Supplementary Appendix).
In univariable analysis, lower pre-transplant testos- terone was correlated with shorter post-transplant OS and PFS, due to higher hazards of both relapse and NRM. Low pre-transplant testosterone was also associated with non- relapse and overall mortality after onset of acute GvHD. The results of the univariable analyses of the training cohort are given in Table 2.
In the multivariable models, lower levels of pre-trans- plant testosterone were significantly associated with worse OS (HR for a decrease of 100 ng/dL, 1.11, P=0.045) and PFS (HR 1.11, P=0.022) (“full” models). Other factors with a statistically significant impact on OS and PFS were patient age and advanced disease stage (Table 3). Notably, lower pre-transplant testosterone was associated with a higher hazard of NRM (CHR 1.25, P=0.013) rather than relapse (CHR 1.06, P=0.277) in patients allografted for AML as revealed by the “slim” models (Table 3).
In contrast to the univariable models (Table 2), no signif- icant association of testosterone with survival after onset of acute GvHD could be observed in multivariable analy-
bAccording to Bacigalupo et al.37 and Bornhäuser et al.38
sis (Table 3). Consequently, and due to the relatively low number of events, no multivariable models were fitted for NRM/relapse following acute GvHD. When pre-trans- plant testosterone as continuous variable was analyzed in multivariable models including age, CRP, BMI, KPS and comorbidities as co-variates, the associations of lower testosterone with worse OS and shorter PFS remained sig- nificant (Online Supplementary Table S5).
Finally, pre-transplant testosterone was assessed and evaluated in a small pilot cohort of female patients allo- grafted for AML in the Heidelberg center (n=32) (Online Supplementary Table S6). As expected, median pre-trans- plant total testosterone serum levels were substantially (20-fold) lower than in males. Importantly, no association of testosterone (per decrease of 10 ng/dL) with any end point was observed in the univariable models (Online Supplementary Table S7).
Pre-transplant testosterone and post-transplant outcome in the confirmation cohort
Patients', disease and transplant characteristics of the confirmation cohort are summarized in Table 1. As com- pared to the training cohort, significantly fewer patients were transplanted for late-stage disease and were allo- grafted after myeloablative conditioning (Table 1). In the confirmation cohort, median pre-transplant total testos- terone serum level was 469 ng/dL (IQR 309-580) (Online Supplementary Figure S1B). The estimated median follow up of survivors was 47 months (95%CI: 39-53). The cumulative incidence of acute GvHD grade 3-4 on day
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