According to our center's strategy, haplo-SCT has primarily been used for patients with relapsed, refractory, or high-risk acute leukemia in the absence of a matched donor. Therefore, a myeloablative conditioning regimen to remove residual disease and TCR-PBSC sources to improve engraftment and GVL effects were administered. Subsequently, the expectation of a high incidence of acute and chronic GvHD related to a mismatched donor, MAC, and the PBSC source (29) motivated us to design a combination regimen consisting of standard-dose ATG plus a modified dose of PTCy (in addition to cyclosporine A) for stronger GvHD prophylaxis (30–32).
The rationale for using the lower dose of PTCy (40 mg/kg, days + 3, +4) in combination with ATG in the context of MAC with PBSCs as the "standard protocol of the center" for all haplo-SCT recipients was based on a prospective study that was conducted on 40 haplo-SCT recipients in our center between 2010 and 2015 and reported as an abstract in BMT 2015 (38).
In this retrospective and single-center cohort, we evaluated the posttransplant outcomes of patients with poor-prognosis acute leukemia undergoing haplo-SCT with our center protocol who received the combination of ATG/PTCy compared with a smaller group with similar characteristics who received the ATG-only protocol. Moreover, to evaluate whether the effect of this protocol is more prominent in myeloid or lymphoid subsets, patients with AML and ALL were separately analyzed after stratification by disease status.
The essential findings of the comparisons between the two arms are as follows: the comparison of outcome events (three-year OS, DFS, RI, and NRM) between the two arms showed that neither arm showed superiority, as the association was not statistically significant, which may be due to the small number of patients in the ATG-based arm. The CI of aGVHD (grade II-IV) was significantly lower in the ATG-PTCy group, although the CI of ANC engraftment at day 30 was better in the ATG group.
Despite a relatively high incidence of aGvHD for all subjects, the occurrence of severe types was infrequent, so aGvHD remained a rare cause of posttransplant mortality, accounting for only 7.41% and 11.1% in the ATG-PTCy and ATG groups, respectively. Interestingly, experiencing aGvHD was an independent protective factor for OS and DFS by preventing relapse (Table 2).
Our results are in agreement with the findings of previous studies comparing the ATG/PTCy combination with other GvHD prophylaxis regimens on posttransplant outcomes, which showed a significant reduction in aGvHD incidence with the combination regimen; nevertheless different doses of ATG or PTCy were used, and there was heterogeneity in the transplant protocols (21, 22, 30–34).
The following articles have explored different doses of ATG/PTCy in combination for haplo-SCT: A low-dose ATG (4.5 mg/kg, total) plus standard-dose PTCy regimen was reported by Law et al. in patients with a low incidence of acute and chronic GvHD (20%, 15%); the 1-year DFS, RI, and NRM were 35.7%, 16%, and 38.2%, respectively (23). Another study demonstrated that standard-dose ATG in conjunction with low-dose PTCy (14.5 mg/kg, days + 3, +4) was associated with reduced GvHD and NRM incidence compared with an ATG-based regimen (20). Yang J et al. applied a different form of combination regimen consisting of a low dose of both ATG (5 mg/kg, total) and PTCy (50 mg/kg, one day) combined with unrelated cord blood that was associated with a lower incidence of GvHD and NRM in comparison to the ATG-based protocol (21).
Subgroup analyses to evaluate AML and ALL patient outcomes stratified by disease status indicated that the 3-year DFS rates of recurrent and refractory disease in patients with ALL (34.5%, 33.3%) were better than those in patients experiencing their first remission of intermediate-high risk ALL (24.6%). We have no explanation for this finding; this discrepancy may be due to the small number of patients in these subsets.
After adjustment of the multivariate model, patients with intermediate- or high-risk AML who received haplo-SCT during the first CR had significantly better outcomes than patients with relapsed and refractory disease. Since all but one intermediate-high risk AML patient who was transplanted in the first remission was included in the ATG/PTCy arm, we compared outcomes (3-year DFS, NRM, and RI of 72%, 23%, and 5%) with two reports of EBMT that were conducted on similar risk groups, as follows:
In the first paper, the 2-year LFS, NRM, and RI of patients with adverse-karyotype AML receiving haplo-SCT during the first CR with different protocols were 53%, 19%, and 27% (8), and in the second report, the 2-year LFS, NRM, and RI were 58%, 23% and 19%, respectively, for patients with intermediate- or high-risk AML receiving haplo-SCT during the first remission (35).
Taken together, the results indicate that patients with intermediate-high risk AML undergoing haplo-SCT during the first CR using our center protocol had better outcomes than other subgroups in the present study and similar populations in other studies (8, 35).
Patients who received haplo-SCT beyond first CR (recurrent disease) were at higher risk for transplant-related morbidity, with the incidence of NRM exceeding 50% and 40% for AML and ALL, respectively (Table 3). In this regard, considering a lower intensity conditioning regimen to reduce the NRM in recurrent patients may be effective, provided there is no residual disease (36).
Given that infectious diseases were the most common cause of death in our study subjects and the high rate of posttransplant CMV reactivation, it seems that an adjustment in the immunosuppression protocol for certain patients (20, 21) and the design of a CMV prophylactic regimen suitable for high-risk transplants (37) could potentially improve NRM by decreasing infectious complications. Moreover, in the refractory group, increased mortality was secondary to increased relapse incidence.
Regarding donor selection for haplo-SCT, it should be noted that the assessment of donor-specific anti-HLA antibodies (DSAs) has been available at our center during the last few years and has produced changes in the donor selection process over time; for example, in the early ATG cohort, there was an extensive use of mothers as donors, whereas in the more recent cohort, siblings were the most commonly used donors.