Reduced relapse rate and improved GVHD/relapse free survival (GRFS) with pharmacokinetics-guided busulfan conditioning regimen for allogeneic stem cell transplantation in adult patients with myeloid hematologic malignancies

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Abstract

The introduction of pharmacokinetic (PK)-guided busulfan in the conditioning regimen has shown beneficial effects, particularly in reducing toxicity, for patients undergoing allogeneic stem cell transplantation (Allo-SCT). However, its impact on relapse rate has been partially investigated and whether this translates into improved graft-versus-host-disease (GVHD)/relapse progression free survival (GRFS) has not yet been reported. We prospectively analyzed 90 patients receiving thiotepa-busulfan-fludarabine (TBF) conditioning regimen with PK-guided busulfan (PK-TBF), targeting an AUC of either 20,000 or 16,000 𝜇mol*min, and compared their outcomes with a historical cohort (n=64) treated with fixed busulfan dose (nPK-TBF). Platelet engraftment occurred significantly earlier in the PK-TBF group: median 20 vs 28 days (p=0.013). The cumulative incidence of relapse (CIR) and grade II-IV acute GVHD were significantly lower in the PK-TBF relative to nPK-TBF cohort: 20% vs 31% (p=0.056) and 13% vs 30% (p=0.009), respectively. Consequently, overall survival (OS) and GRFS were significantly improved with PK-TBF relative to nPK-TBF: at 3-years, 61% vs 47% (p=0.025) and 49% vs 34% (p=0.019), respectively. By multivariable analysis, PK-TBF remained an independent predictor of relapse, OS, and GRFS. Outcomes did not differ between PK-TBF AUC targets of 20,000 and 16,000 𝜇mol*min with respect to GVHD or non-relapse mortality (NRM); however, the higher AUC (20,000 𝜇mol*min) cohort was associated with a significant reduction in CIR (at 3 years: 0% vs. 25%, p=0.035). In conclusion, PK guided TBF significantly improves outcome of patients receiving Allo-SCT and higher busulfan exposures may enhance disease control without increasing toxicity.