Page 303 - Haematologica April 2020

PBSC with ATG vs. BM
1.0, P=0.07). Factors associated with NRM on multivari- ate analysis included older age at transplantation (HR=1.4, 95% CI: 1.3-1.5, P<0.001) and secondary AML (HR=1.4, 95% CI: 1.1-1.9, P=0.01) while a more recent transplant year was associated with lower NRM (HR=0.8, 95% CI: 0.7-1.0, P=0.03).
OS and LFS
The 2-year OS and LFS were 64% (95% CI: 58-70%) and 58% (95% CI: 53-64%) in BMT without ATG patients versus 67% (95% CI: 64-69%, P=0.3) and 60% (95% CI: 58-62%, P=0.7) in PBSC with ATG patients, respectively (Figure 2A-B). After adjusting for potential confounding factors, the use of PBSC with ATG was associated with a better OS (HR=0.8, 95% CI: 0.6-1.0, P=0.04) than with BM, but there was no significant dif- ference in LFS between the groups (HR=0.9, 95% CI: 0.7- 1.1, P=0.2). As well as being in the BMT group, older age was significantly associated with a poorer OS (HR=1.2, 95% CI: 1.1-1.3, P<0.0001) and a worse LFS (HR=1.1, 95% CI: 1.1-1.2, P<0.0001).
Causes of death were comparable in both groups expect for a higher frequency of infectious-related death in the PBSC with ATG group (23% vs. 11%) (Online Supplementary Table S3).
GRFS
The 2-year GRFS was 43% (95% CI: 37-49%) versus 50% (95% CI: 47-52%) in BMT without ATG and PBSC with ATG recipients, respectively ( P=0.002) (Figure 2F). This was confirmed in multivariate analysis including data from all patients (HR=0.8, 95% CI: 0.6-0.9, P=0.001) as well as in further sensitivity analysis restrict- ed to patients given a combination of a calcineurin inhibitor and methotrexate as GvHD prophylaxis (HR=0.8, 95% CI: 0.6-0.9, P=0.01). Finally, older patient age was also associated with worse GRFS (HR=1.1, 95% CI: 1.0-1.1, P=0.004) in the whole cohort of patients.
Discussion
Several studies have now established that the use of PBSC (without ATG) instead of BM is associated with a high incidence of (severe) cGvHD affecting the long- term well-being of the patients.2,5 In contrast, several phase III trials have demonstrated a beneficial impact of ATG on cGvHD.12 Here, we compare the outcomes of AML patients given BMT without ATG versus PBSC with ATG, in the setting of AML in first or second CR. We elected to restrict the analyses of patients given grafts after myeloablative conditioning since it was a inclusion criteria in most phase III ATG studies, although many AML patients are nowadays transplant- ed following reduced-toxicity regimens.20,21 Several observations can be made.
First, the use of PBSC with ATG was associated with a lower incidence of cGvHD both in the MSD and MUD datasets. This clearly demonstrates that ATG administra- tion is able to counterbalance the high risk of cGvHD associated with the use of PBSC (instead of BMT with- out ATG).
Importantly, the incidence of relapse was not signifi- cantly different in BMT without ATG and in PBSC with ATG patients in both datasets. This may appear surpris- ing given the tight association between cGvHD and graft-versus-leukemia effects, and is consistent with most phase III ATG trials showing,22-24 a reduction of cGvHD without an increase in the relapse risk.12 Similar findings were observed in the RIC setting in a large registry study.25
Given the data of the Soiffer et al. phase III study showing detrimental effects of ATG in patients given TBI-based conditioning regimen,11 we investigated whether, in our study, there was a statistical interaction between graft type and the risk of relapse and the use of TBI in the conditioning regimen. Interestingly, we observed a lower risk of relapse only in the subgroup of patients given TBI-based conditioning suggesting no adverse effects of ATG in patients given TBI-based con- ditioning. These data are in concordance with recent observations reported by our group.26
The main endpoint of our retrospective study was GRFS, a relatively new composite endpoint which aims at capturing the rate of cure without ongoing transplant- related morbidity.27 We observed a non-significant differ- ence in GRFS with the two strategies in the cohort of patients given grafts from MSD, and a significantly bet- ter GRFS with PBSC with ATG in the cohort of patients given grafts from MUD. We thus advocate that our data might support the use of PBSC with ATG rather than BMT without ATG, in AML patients in CR at transplan- tation.
An interesting finding of our study was an increasing relapse incidence (but decreasing non relapse mortality incidence) with more recent transplantations. This might be due to a higher proportion at high risk of relapse (as example more patient with persistent minimal residual disease at transplantation) in more recent years of trans- plantation. Unfortunately, we do not have data on the MRD status at transplantation for many patients includ- ed in this survey.
There are some limitations of the study such as its design (it is however unlikely that a prospective random- ized phase III trial will address this question in the near future), the lack of data on mutational AML landscape and minimal residual disease, a high proportion of miss- ing cytogenetic data, the lack of ATG dose data for sev- eral patients, and some imbalances between the groups. However these imbalances were adjusted for in the mul- tivariate Cox models. The strengths of the study are the number of patients in each group and their relative uni- formity (one single disease, all patients in first or second CR at transplantation, no HLA-mismatches, only mye- loablative conditioning regimen).
In conclusion, our data suggest that PBSC transplanta- tion with ATG results in comparable (in case of MSD) or significantly better (in case of MUD) GRFS than BMT without ATG in patients with AML in CR receiving grafts after myeloablative conditioning. These data might support the use of PBSC with ATG compared to BMT without ATG in patients receiving grafts from MSD or MUD after myeloablative conditioning as treat- ment for AML in CR.
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