Page 298 - Haematologica April 2020

F. Baron et al.
dence of cGvHD, similar OS, and better patient-reported outcomes at 5 years after transplantation than those ran- domized to the PBSC arm.4,5 This might suggest that, at least in the MUD setting, BM may be preferred over PBSC as a stem cell source in patients receiving grafts after mye- loablative regimens. In concordance with these findings, a recent European Group for Blood and Marrow Transplantation (EBMT) study observed a better GvHD- free relapse-free survival (GRFS) with BM than with peripheral blood (PB) as the stem cell source.6
In the last two decades, five phase III trials have assessed the impact of anti-thymocyte globulins (ATG) on transplan- tation outcomes in patients given grafts (mainly PBSC) from MSD (n=1)7 or MUD (n=4).8-11 These five trials demonstrat- ed a lower incidence of cGvHD with ATG.12 Two of three trials assessing the impact of ATG on GRFS13 observed bet- ter GRFS in patients randomized to ATG,7,10 while the study by Soiffer et al. failed to demonstrate this effect.11 ATG was also found to improve GRFS in a registry study including data from patients given grafts from HLA-identical siblings after myeloablative fludarabine + busulfan regimens.13
These findings prompted us to compare transplantation outcomes in AML patients following BMT without ATG versus PBSC transplantation with ATG in the first or sec- ond complete remission (CR).
graft type on transplantation outcome. These Cox models were adjusted for disease status at transplantation, female donor to male recipient or not, CMV serostatus, use or not of total body irradiation (TBI), year of transplantation, age at transplantation, primary versus secondary AML, and cytogenetic risk. In order to take into account the center effect, we introduced a frailty for each center into the model, as previously reported.18,19 Specifically, we introduced a random effect (also named frailty effect) in the Cox multivariate models. Then, the same random effect was shared by all patients within the same center. In order to assess whether there was a statistical interaction between the year of transplantation and the association between BMT with- out ATG versus PBSC with ATG and the incidence of relapse, we introduced the interaction term between cell source and year as a binary variable (with the median year by group as the cut-off) in the Cox multivariate model for relapse. Results are presented as hazard ratios (HR) and 95% confidence intervals (95% CI). The HR for year of transplantation corresponded to a 5-year increase and to a 10-year increase for the age at transplantation. As planned in the synopsis, the analyses were done separately for MSD and MUD. The interaction between graft type (i.e. BM without ATG or PBSC with ATG) and donor type (MSD versus MUD) was confirmed for several outcomes (data not shown).
Results
BM without ATG versus PBSC with ATG in MSD recipients
Patients
A total of 2,654 MSD recipients met the inclusion/exclusion criteria, comprising 1,633 BM with- out ATG patients and 1,021 PBSC with ATG patients (Table 1). In comparison to BM without ATG recipients, PBSC with ATG patients were older (median 48 years vs. 40 years old), were transplanted more recently (median year of transplantation 2014 vs. 2008), less likely to have a good cytogenetic risk (10% vs. 16%), more likely to have secondary AML (11% vs. 6%), less frequently received TBI in the conditioning regimen (12% vs. 32%), and were more frequently male patients receiving grafts from female donors (25% vs. 22%).
GvHD
The 100-day incidence of grade 2-4 aGvHD was 27% (95% CI: 25-29%) in BM without ATG recipients versus 18% (95% CI: 16-20%) in PBSC with ATG patients (P<0.001). For grades III-IV, the figures were 9% (95% CI: 8-11%) and 6% (95% CI: 4-7%), respectively (P=0.002). In multivariate analyses, the difference for grade II-IV aGvHD between PBSC with ATG versus BM without ATG was no longer statistically significant (HR=0.8, 95% CI: 0.7-1.1, P=0.12) (Table 2) while the use of TBI in the conditioning was associated with a higher incidence of grade II-IV aGvHD (HR=1.4, 95% C1: 1.1- 1.8, P=0.004). In contrast, a more recent transplantation year was associated with a lower incidence of grade II-IV aGvHD (HR=0.8, 95% CI: 0.7-0.9, P=0.0004).
At 2 years the CI of cGvHD was 34% (95% CI: 31- 36%) in BM without ATG recipients versus 30% (95% CI: 27-33%) in PBSC with ATG patients (P=0.02) (Figure 1E). This association remained statistically significant on multivariate analysis with a lower risk of cGvHD among PBSC with ATG recipients (HR=0.7, 95% CI: 0.6-0.9,
Methods
Ethics
The scientific board of the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) approved this research project. The study was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines.
Inclusion/exclusion criteria and study endpoints
Inclusion criteria included adult patients, de novo or secondary AML, myeloablative conditioning, MSD or 10/10 HLA-matched unrelated donors (MUD), first or second CR, first allo-transplan- tation from 2000 to 2017 at an EBMT-affiliated center, and either BM without ATG, or PBSC with ATG. Exclusion criteria consist- ed of in vitro T-cell depletion of the graft, and prior administra- tion of alemtuzumab. The primary endpoint was GRFS. Secondary endpoints included grade II-IV GvHD, RI, non- relapse mortality (NRM), leukemia-free survival (LFS) and OS.
Statistical analyses
Myeloablative conditioning was defined as use of ≥ 6 Gy TBI, busulfan > 8 mg/kg, or melphalan > 140 mg/m2 as previously reported.14 The cytogenetic AML risk was determined as previ- ously reported.15,16
NRM was defined as death without prior or current disease recurrence. Events in the composite endpoint GRFS included grade III-IV aGvHD, extensive cGvHD, relapse or death as pre- viously reported.17
OS, LFS and GRFS were estimated using the Kaplan-Meier estimates. Cumulative incidence functions (CIF) were used for RI and NRM in a competing risk setting, since death and relapse are competing together. In estimating the cumulative incidence of aGvHD and cGvHD, we considered relapse and death to be competing events. Univariate analyses were done using Gray’s test for CIF and the log-rank test for GRFS, OS and LFS. Since there were some imbalances between the groups we performed multivariate Cox models to further determine the impact of the
1140
haematologica | 2020; 105(4)