To date, the question of the best combination of GvHD-preventing drugs in the MUD-PBSCT remains unanswered. ATG has become the standard of care in this setting, while PTCY is increasingly used potentially replacing ATG.8–10 The conceptual difference between ATG and PTCY is that the former depletes T-cells in a dose dependent manner, whereas the latter should eliminate only the proliferating alloreactive donor lymphocytes while preserving the resting memory T-cells. The rationale of combining ATG and PTCY is to further reduce GvHD. Theoretically, such a combination is not synergistic as ATG depletes the T-cells which should allo-react and proliferate in order to become prone to cyclophosphamide elimination.18 To our knowledge, this is the first large series study demonstrating the feasibility of the PTCY + ATG combination in MUD-PBSCT and analyzing the impact of adding ATG to PTCY in this setting.
We found that PTCY + ATG can be safely given in MUD-PBSCT without compromising engraftment and without modifying the risk of NRM when compared to PTCY-treated patients. Our findings concur with single center studies of HLA-matched PBSCT reporting reliable donor cell engraftment and low NRM rates with PTCY + ATG similar to standard CIS-treated historical controls.19–23 We cannot exclude the possibility that addition of ATG to PTCY induced more viral reactivations and specific morbidity as such information could not be captured in our retrospective analysis. Nevertheless, both the incidence of NRM (any cause) and NRM due to infections did not differ between PTCY and PTCY + ATG treated patients. As PTCY is associated with an increased risk of cytomegalovirus (CMV) infection, it remains to be seen whether the low NRM rates of the PTCY + ATG combination reported here will be replicated in centers where access to PCR-guided pre-emptive or prophylactic antiviral therapy is not ideal.24
Though the univariate analysis showed an improvement of extensive cGvHD when ATG was added to PTCY, this effect was not apparent on multivariate analysis. Indeed, the Cox proportional-hazards model did not detect any difference between PTCY + ATG versus PTCY patients with respect to both aGvHD and cGvHD (of all grades). In contrast, ATG has been shown in randomized studies to reduce GvHD, especially cGvHD, when added to standard CIS in MUD-PBSCT.4–6 One can assume that PTCY or ATG alone could control GvHD efficiently, making a combined PTCY + ATG in vivo T-cell depletion redundant. In support of this, our PTCY-treated patients who did not receive ATG (n = 421) had a remarkably low cumulative incidence of grade III-IV aGvHD (9.6%) and extensive cGvHD (21%). Similar low severe aGvHD grade III-IV (2–6%) and extensive cGvHD (19–22%) rates have been recently reported in prospective HLA-matched (MRD/MUD) PTCY-based RIC-PBSCT studies.25,26 It is of note that in our series only 2.4% of patients did not receive any CIS; PTCY without any CIS has resulted in a high incidence of aGvHD in HLA-matched RIC-PBSCT.27,28
The addition of ATG could potentially be detrimental to the GVL effect. However, no differences were observed in REL rates between groups, with adverse cytogenetics remaining the most important factor affecting REL in the multivariate analysis. This result should be taken with caution, as we focused only on AML patients transplanted in CR with less risk of REL. In agreement with our results, previous studies focusing on such populations (AML, CR) found that ATG given at the EBMT-recommended dose29 (as expected to have been used in our transplanted cohort) does not impact REL.30,31 Another explanation for the comparable REL rates in the PTCY and PTCY + ATG groups could be related to their differential reconstitution of natural killer (NK) cells. Makanga et al. suggested that PTCY + ATG versus PTCY-treated haploidentical recipients have a faster reappearance of NK cells which mature more rapidly and thus that the addition of ATG may have restored the possible delayed NK-mediated GVL effect seen with PTCY alone.15 Future studies should aim to define more precisely the diverse and multifaceted effects of the PTCY + ATG combination on immune reconstitution.
Considering the absence of any impact of the addition of ATG to PTCY on GvHD, NRM, and REL, it is not surprising that there was no significant difference in survival (OS, LFS, GRFS) between PTCY and PTCY + ATG treated patients. Clinically, these results call into question the rationale of intensifying GvHD prophylaxis with ATG in MUD-PBSCT when PTCY is used, a finding which should be validated in prospective trials. Of note, our study does not evaluate whether ATG or PTCY is better in MUD-PBSCT. While a prospective study answering this question is ongoing,9 retrospective EBMT studies have suggested a superiority of PTCY over ATG in terms of less aGvHD and better GRFS in 1 HLA-mismatched (9/10) unrelated HCT and comparable outcomes in well-matched (10/10) MUD-HCT.8,10
This study has all the inherent limitations of a retrospective registry-based analysis. Although we focused on a relatively uniform patient population (AML, CR, PBSCT, MUD) and tried to overcome further heterogeneity through multivariate modelling, there are still unmeasured factors (e.g. time of CIS withdrawal) that could not be captured and adjusted for. Notwithstanding, this is the largest patient series showing that ATG can be safely combined with PTCY in the MUD-PBSCT setting enabling reliable donor cell engraftment, resulting in low rates of NRM and without detrimental effect on disease control in AML patients transplanted in CR. However, the addition of ATG to PTCY in this setting does not seem to provide any benefit in terms of GvHD reduction, meaningful improvement of quality of life (measured as better GRFS) or better survival. As the combination of ATG and PTCY is a feasible strategy for GvHD prevention in MUD-PBSCT, futured prospective studies might prove that such a dual PTCY + ATG in vivo T-cell depletion in the early post-transplant period could allow the sparing of long-term immunosuppression with CIS agents.