Graft Versus Host Disease Prophylaxis with Tacrolimus, Sirolimus and MMF in Patients Undergoing Reduced Intensity Conditioning Allogeneic Transplantation

I ntroduction

GvHD remains the leading cause of toxic morbidity and mortality (NRM) after allo-HSCT. Different prophylaxis schemes have been developed in the context of reduced intensity conditioning (RIC). In 2019, the multicenter phase 3 trial NCT01231412 compared GvHD prophylaxis based on the calcineurin inhibitor (CNI) CSA plus MMF with (experimental arm) or without (control arm) sirolimus. The triple combination was associated with a lower risk of aGvHD and longer survival and, in the authors' opinion, could constitute a new standard (Sandmaier, Lancet Oncol 2019). We present the largest real-world experience to date with the triple prophylaxis scheme in the context of allo-HSCT with RIC from matched-related (MRD), matched-unrelated (MUD) and mismatched URD (mmURD).

Material and Methods

Prospective study of 159 consecutive patients receiving an allo-HSCT after RIC between 09/2019 and 12/2022 at two centers using the tacro/siro/MMF as GvHD prophylaxis. The primary endpoint was the cumulative incidence of aGvHD grades 2-4. As secondary variables: cGvHD at 1 and 3 years, NRM at +100, +1 year and overall NRM, OS at 1 and 3 years, PFS at 1 and 3 years and GRFS at 1 and 3 years.

Results

Baseline characteristics are shown in Table 1. Note the high percentage of patients with high/very high rDRI or HCT-CI of 3+. In 38.4% an URD was used as source of progenitor cells and in 20.8% it was a MMURD. The median follow-up was 20 months (3-40). There were 4 (2.5%) graft failures (2 of them secondary). Median neutrophil and platelet engraftment was 16 days (3-175) and 12 days (7-210). The risk of relapse was 31% and 35% at 1 and 3 years. NRM at day +100, + 1 year and overall NRM was 4.4%, 8.17% and 9.4%. The causes of NRM were GvHD +/- infection in 73%, with other causes being TMA (n=1) and SOS (n=1). The cumulative incidence (CI) of grades 2-4 aGvHD 2-4 at day +100 and +180 was 29.7% and 32.3%, including 40% of upper gastrointestinal tract involvement which resolved with topical treatment. The CI of grades 3-4 aGvHD at day +100 and +180 was 12.8% and 16% (3.14% grade 4). The CI of cGvHD at 1 and 3 years was 21.5% and 51.2% and for moderate/severe it was 13.9% and 36.6%. OS at 1 and 3 years was 70.3% and 61%. Median PFS was 35 months, with 1- and 3-year PFS of 60% and 49%. The GRFS at 1 and 3 years was 44% and 32%. The risk of grades 2-4 aGvHD was significantly higher among patients receiving allo-HSCT from MMURD (at d+100 and +180, 35.4% and 39.9%) vs matched donors (at d+100 and +180, 55.5% and 61%, p=0.04). The same variable also influenced on OS (at 1 and 3 years 73.3% vs 64.6% and 57.6% vs 37.8% for matched vs mismatched donors, respectively; p=0.013) (Figure 1). On the other hand, low and intermediate DRI patients had a significantly better OS as compared to high/very high rDRI patients (at 1 and 3 years 80.8% and 80.8% for low vs 86.7% and 78.3% for intermediate vs 56.9% and 55.1% for high and very high; p=0.013) (Figure 1).

Conclusions

Triple prophylaxis with Tacro-Siro-MMF shows excelent results in terms of NRM, GvHD and survival in a high-risk and elderly population in the context of allo-HSCT from matched-related (MRD) and matched-unrelated (MUD) donors. The subgroup of patients receiving allo-HSCT from MMURD showed a high incidence of overall and grade 3-4 aGvHD with impact on OS, being a group that will probably benefit from other prophylaxis strategies.