Despite the existence of multiple HLA mismatches, Haplo-HCT has now become a standard of care in patients lacking an HLA-identical donor, particularly due to the use of in vivo T-cell depletion (TCD) that allows low rates of GVHD. To date, the most commonly used in vivo TCD platform in the United States and Europe is based on PTCy but the Chinese experience with ATG also highlighted the feasibility and efficacy of this strategy in the Haplo setting. However, initial experiences with in vivo TCD in Haplo-HCT were mainly based on the use of bone marrow as the stem cell source, in order to reduce the risk of GVHD .
Use of PBSC has been associated with a higher risk of acute and particularly cGVHD in all donors settings . However, donor collection from PB is more easily manageable and has also been associated in several studies with faster engraftment and the graft-versus-leukemia effect . Therefore, use of PBSC has significantly increased worldwide . The addition of ATG to standard immunosuppressive agents in both the matched sibling and unrelated donor settings has been shown to reduce the incidence of GVHD, particularly its chronic form, and also to allow a more rapid withdrawal of immunosuppression. .
More recently, use of PBSC in Haplo-HCT has also increased significantly and strategies of GVHD prevention have included dual in vivo TCD with PTCy and ATG .
The Beijing group from China initially introduced the GIAC protocol using a combination of G-CSF-priming of the donor, intensified immunosuppression, ATG, and combination of T cell-replete bone marrow plus PBSC, showing low incidences of GVHD . More recently, they compared the GIAC protocol with ATG alone to ATG and low-dose PTCy, showing better GVHD prevention with the dual in vivo TCD approach .
Duléry et al. reported Haplo-PBSC transplant outcomes in patients receiving TBF as the conditioning regimen and dual in vivo TCD with PTCy and ATG in 51 patients, showing a low incidence of aGVHD without affecting other outcomes, thus highlighting the feasibility of this schedule .
More recently, a multicenter retrospective study from El Cheikh et al. explored the impact of adding ATG to PTCy versus PTCy alone in Haplo-PBSC with TBF for various hematologic malignancies, showing no significant differences between the two approaches for any transplant outcome .
In the current retrospective analysis, we evaluated the impact of the addition of ATG to PTCy in the setting of Haplo-PBSC as compared to PTCy alone in a population of AML patients in CR, all receiving CsA and MMF in addition. Furthermore, the two cohorts were well balanced for most demographic characteristics, including distribution of conditioning regimens. Our results confirm the feasibility of such a strategy in the Haplo-PBSC setting, as previously reported, with both the MAC and RIC regimens.
Of note, we observed a significantly higher cumulative incidence with faster neutrophil engraftment when adding ATG to PTCy. Previous studies comparing ATG to PTCy in different donor settings showed that use of ATG provides a more rapid and higher rate of neutrophil engraftment . Therefore, in the Haplo-PBSC setting, addition of ATG to PTCy may promote the host-versus-graft reaction and favor a faster engraftment.
Importantly, we found that addition of ATG to PTCy resulted in a lower risk of cGVHD of all grades (but not of extensive cGVHD) without differences for other transplant outcomes. This result confirms, as previously reported in other donor settings, that ATG is a valid agent in GVHD prevention, particularly in its chronic form, due to the long-term inhibitory effect on both B and T cells that play a pivotal role in the development and the pathogenesis of GVHD .
Major concerns with the use of ATG are the risk of delayed immune reconstitution, higher mortality due to infection and higher risk of disease relapse . In a single-center analysis from Canada, addition of a total ATG dose of 4 mg/kg to PTCy in Haplo-PBSC with the use of a RIC regimen resulted in a 1-year NRM of 38.2% that was mainly attributed to infection complications . In an attempt to reduce NRM, the same group tried a dose reduction from 4 to 2 mg/kg, which resulted in a higher incidence of aGVHD with no impact on other transplant outcomes . Importantly, in our study we did not observe any differences in the cumulative RI or in NRM with the addition of ATG, with infection mortality being 35% in both groups. Furthermore, although different doses of ATG were used in the ATG+PTCy group, the low number of patients prevented us from exploring the impact of ATG dose on transplant outcomes.
Our results should be taken with caution, due to the retrospective nature of the study and the consequent lack of certain data that may have confounded the results. For example, criteria guiding physicians in patient allocation to a specific regimen, absence of specific data on immune reconstitution, incidence of non-fatal infections, the detailed AML risk stratification, a potential center effect when using ATG and the post-transplant strategies to prevent or treat disease relapse. Furthermore, we also acknowledge the relatively small number of patients included in the ATG+PTCy cohort and the short follow-up.