The baseline characteristics of the study population are presented in Table 1. A total of 2123 patients were included, from which 1540 (73%) received rATG, and 583 (27%) received PTCy as a GVHD prophylaxis.

Overall, the majority of patients was transplanted for acute leukemia (58.6%), myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) (25.6%) or lymphoma (15.1%). A high proportion of patients had a low/intermediate Disease Risk Index (DRI, 72%), and myeloablative conditioning (MAC) was more frequently performed (53.9%) than reduced intensity conditioning (RIC).

Patients in the rATG group were older, with a median age of 56.1 years (IQR 44.7, 63.8) vs. 51.7 years in the PTCy group (IQR 40.0, 62.2) (p ≤ 0.001), with a similar proportion of males (58% in rATG vs. 60% in PTCy, p = 0.48), and less recent transplants (p < 0.01), along with a significantly lower use of TBI (14.3% vs. 20.4%, p < 0.01). The remaining parameters were balanced between the two groups.

Median follow up was 2.0 years (95% CI [2–2.2]) in the PTCy arm and 2.4 years (95% CI [2.2–2.6]) in the rATG arm.

Univariate outcomes are shown in Fig. 1 and Table 2. The results of the multivariate analyses are summarized in Table 3.

A Non-relapse mortality; B overall survival; C relapse incidence; D progression-free survival; E GVHD-free relapse-free survival.

Patients receiving PTCy had a significantly lower NRM as compared to patients receiving rATG (2 years incidence: 18% vs. 24.9%; HR: 0.74 [95% CI 0.56–0.97], p = 0.028). Similarly, OS and PFS showed a statistically significant and clinically meaningful benefit for PTCy arm, with a higher OS (2 years incidence: 65.7% vs. 55.7%; HR: 0.77 [95% CI 0.65–0.90], p < 0.001), and a higher PFS (2 years incidence: 59.1% vs. 48.8%; HR: 0.78 [95% CI 0.67–0.91], p = 0.001). RI did not differ significantly between the two groups, however, there was a trend toward a lower relapse rate in the PTCy arm vs. the rATG arm (2 years incidence: 22.9% vs. 26.2%; HR: 0.82 [95% CI 0.67–1.01], p = 0.068) (see Fig. 1).

Relapse of the underlying malignancy was the most frequent cause of death, accounting for 287 (44%) of total deaths in both arms, followed by NRM causes: infections (161 [19%]), GVHD (150 [18%]) and other alloSCT-related causes (150 [9%]) of total deaths. Secondary malignancies contributed to ~1% of total deaths, proportion for each arm are presented in Table 4.

After conducting an additional multivariate cox analysis, adjusting for HLA mismatches location additionally to the previous factors, we found no hazard ratio (HR) for HLA mismatches to be statistically significant. This indicates that the differences in outcomes are not attributable to HLA-A, B, or C mismatches in our context. Furthermore, our results consistently demonstrate a significant benefit in favor of PTCy relatively to ATG. Specifically, we observed a notable reduction in non-relapse mortality (NRM) associated with PTCy compared to ATG, with a hazard ratio (HR) of 0.66 [CI 95%: (0.49–0.88); p value: 0.005], similarly there was a significant improvement in overall survival (OS) for PTCy relatively to ATG [HR: 0.69, CI 95%: (0.56–0.83); p value < 0.001], we also observed a reduced risk for progression-free survival (PFS) in PTCy relatively to ATG [HR: 0.71 CI 95%: (0.59–0.86); p value < 0.001]. These results were further supported by the fact that no significant interaction term between PTCy vs. ATG and Mismatch Location has been found, suggesting that the beneficial effect of PTCy over ATG is consistent across different HLA mismatch subgroups.

No significant difference was observed in acute and chronic GVHD outcomes between the two groups (see Fig. 2). The incidence of acute GVHD grades II–IV in patients receiving PTCy vs. rATG (100 days incidence: 29.9% vs. 32.5%; HR: 0.83 [95% CI 0.66–1.04], p = 0.11), and the incidence of severe acute GVHD grades III–IV (100 days incidence: 11.4% vs. 13.8%; HR: 0.78 [95% CI 0.59–1.05], p = 0.1), showed no significant difference. Similarly, overall chronic GVHD for patients receiving PTCy vs. rATG (2 years incidence: 31.7% vs. 30.3%; HR 0.95 [95% CI 0.74–1.22], p = 0.67), as well as extensive chronic GVHD (2 years incidence: 12.7% vs. 14.2%; HR 0.83 [95% CI 0.63–1.10], p = 0.20) were not statistically different.

A Acute GVHD II–IV, B acute GVHD III–IV, C chronic GVHD all grades, D extensive chronic GVHD.

GRFS was significantly higher in the PTCy arm compared to the rATG arm (2 years incidence: 46% vs. 35.3%; HR: 0.80 [95% 0.68–0.94], p = 0.006) (see Fig. 1).