Introduction The application of post-transplant cyclophosphamide (PTCy), as GvHD prophylaxis, has been increasingly used in matched related and unrelated donor transplants with encouraging outcomes in terms of GvHD control, although at the cost of increased toxicity. In our study, we sought to investigate whether a reduced-dose PTCy regimen could provide effective GvHD prophylaxis while minimizing toxicity. This study reports results of a longer follow-up period (median follow-up of 27 months), focusing mainly on the safety and efficacy of the scheme.

Materials and Methods A prospective, single-centre study was conducted to assess the safety and efficacy of reduced-dose PTCy (15 or 25mg/kg), combined with low-dose alemtuzumab (5mg/day for 2 days) and cyclosporin, as GvHD prophylaxis in 9/10 mismatched unrelated (MMUD) peripheral blood stem cell transplant (PBSCT) setting (study group). A control group of patients who underwent 9/10 MMUD PBSCT and did not receive PTCy as part of GvHD prophylaxis, was included in the study. The cumulative incidence of acute and chronic GvHD, along with the relapse rates and survival outcomes (NRM, OS, GRFS) were analysed.

Results Sixty-three patients were included in the study group, with 33/63 belonging to the 15mg/kg (subgroup 1) and 30/63 to the 25mg/kg (subgroup 2) groups, whereas 31 patients were included in the control group. The baseline characteristics between the groups were similar, with the exception of age (significantly younger patients in the control group, 43 vs 51 years, p=0.04) and a trend toward a lower DRI in the control group (55% vs 40% with low/intermediate DRI, p=0.07). In terms of engraftment, no difference was noted in the neutrophil or platelet engraftment between the two groups. Similar rates of CMV and EBV reactivation and of hemorrhagic cystitis were noted between the two groups, as well between the two subgroups.

The cumulative incidence (CI) of acute GvHD (aGvHD) grade II-IV and III-IV was significantly higher in the control group compared to subgroups 1 and 2 (48%, 29% and 20%, p=0.02, and 29%, 13% and 3%, p=0.01, respectively). Furthermore, within the PTCy-treated patients, those in the subgroup 1 had a significantly higher incidence of aGvHD grade II-IV and II-IV than those in the subgroup 2 (p-0.04 and p=0.01, respectively). In multivariate analysis, the type of GvHD prophylaxis was the only variable significantly associated with the risk of aGvHD. The CI of chronic GvHD (cGvHD) of any grade was: 17% (95% CI, 6%–30%) in the Control group, and 20% (95% CI, 10%–32%) in the Study group. The CI of moderate-to-severe cGvHD was 11% (95% CI, 3%–24%), and 15% (95% CI, 7%–26%) in the Control and Study group, respectively. There was no significant difference in the incidence of either overall or moderate-to-severe cGvHD between the Control and Study groups, or between the PTCy subgroups.

The CI of NRM was significantly higher in the control group, compared to the study group (45% vs 19%, p=0.06). Patients in the subgroup 1 had significantly higher NRM compared to patients in the subgroup 2 (p=0.02). The use of PTCy and the patient age (above vs below the median) were the only factors associated with increased NRM in a multivariate analysis. The CI of relapse was similar between the study and the control groups (25% vs 26%, p=ns). Patients in the subgroup 1 showed a trend toward reduced relapse compared to those in the subgroup 2 (15% vs 36%, p=0.05). Multivariate analysis for relapse identified DRI as the only parameter associated with relapse incidence. In terms of survival outcomes, patients in the PTCy group demonstrated significantly improved RFS, OS, and GRFS compared to the control group (56% vs 34%, 63% vs 35% and 48% vs 25%, respectively). The 25mg/kg subgroup showed favorable OS and GRFS (71% and 45%, respectively), while the 15mg/kg group had a lower relapse rate (15%), supporting a risk-adapted approach.

Discussion Our findings suggest that low-dose PTCy combined with alemtuzumab is effective in reducing both acute and chronic GvHD, with favorable OS, GRFS, and relapse rates. Moreover, the ability to tailor PTCy dosing based on disease and relapse risk could allow for a personalized approach to GvHD prevention. These results warrant validation in larger prospective, randomized studies and exploration of novel PTCy-based combinations, potentially paving the way for new standards in GvHD prophylaxis.

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2025
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