Introduction Busulfan represents a cornerstone of conditioning regimen employed before allogeneic stem cell transplantation (Allo-SCT), is usually associated with fludarabine and its efficacy is hampered by several side effect, such as veno-occlusive disease (VOD), neurologic toxicity and infections. This was especially the case when a fixed dose of busulfan was used: lower dosages were associated with higher risk of graft failure and leukemia relapse, while increased risk of toxicities and GVHD were observed at higher systemic exposures (Andersson 2008, Slattery 1997, Liu 2013). In the attempt of optimizing the risk-benefit balance of busulfan, a pharmacokinetics-guided (PK) approach was developed, demonstrating a narrow window of opportunity in terms of area under the curve (AUC), comprised between 4000 and 6000 mol/min/day. Anderson et al(2017) compared Busulfan-fludarabine (Bu-Flu) with AUC 6000 mol/mid/day relative to 130 mg/mq/day fixed dose and demonstrated that a PK-guided approach was significantly advantageous in terms of reduced relapse, improved progression (PFS) and overall survival (OS) for patients with myeloid malignancies, either AML or myelodysplastic syndromes (MDS). In the recent years, several studies have evaluated Bu-Flu augmentation with thiotepa to reduce the risk of graft rejection and disease relapse. Our group has developed a pharmacokinetics-guided TBF conditioning, setting AUC at 16000 mol/min in four days for patients with lymphoid or myeloid malignancies and showing a promising 1-year cumulative incidence of relapse (CIR) of 6% and non-relapse mortality (NRM) of 13% (Bramanti 2021). Here we extend our previous findings by presenting results only in patients with myeloid malignancies, testing two different dosages of busulfan either at 16000 or 20000 mol/min, and by comparing a PK-guided approach relative to a fixed dose (65 or 130 mg/mq/day for 4 days) at our institution.

Methods This study included all patients who received PK-guided TBF conditioning (PK-TBF) before Allo-SCT at our Institution between January 2019 and December 2023. This retrospective study received Institutional Review Board approval (ONC/OSS-05/2020). PK-guided TBF condition was further compared with a historical group that received fixed-dose TBF (no PK-TBF) between January 2012 and December 2018. Primary endpoint was represented by cumulative incidence of relapse (CIR); secondary endpoints were engraftment, infections, NRM, OS, PFS, acute and chronic graft-versus host-disease (GVHD) and GVHD/relapse free survival (GRFS)

Results 90 patients received PK-TBF, while 60 had non PK-TBF. AML and MDS were represented in 66% and 34% of PK-TBF vs 78% and 22% of no PK-TBF (p=0.091). Median age was 60 relative to 63 years-old in PK vs no PK-TBF (p=0.181). The two cohorts were well-matched in terms of high/intermediate/low risk disease according to ELN and IPSS-R score (p=0.416), pre-transplant disease status (p=0.1), donor type (either MRD, UD or Haplo, p=0.087), GVHD prophylaxis (ATG vs PT-Cy, p=0.141), HCT-CI (<3 vs >3, p=0.684). Median follow-up was significantly longer for no PK-TBF relative to PK-TBF (88 vs 33 months) and bone marrow (BM) stem cells were more frequently employed as graft source after PK-TBF conditioning (p<0.01).

Engraftment occurred earlier after PK-TBF relative to no PK-TBF (ANC median days 16 vs 18, p=0.061, PLT median day 20 vs 28 days, p=0.013). This translated in lower frequency of bacterial infection during neutropenic phase (7% vs 28%, p<0.001).

3-years CIR was lower after PK vs no PK-TBF (20% vs 31%, p=0.056) and this advantage was more pronounced in the subgroup of patients treated with ATG as GVHD-prophylaxis. 3-years PFS and OS were significantly higher after PK-TBF (58% and 61%) relative to no-PK TBF (41% and 47% respectively; p< 0.05). 6-months CI of acute GVHD was significantly lower in the PK-TBF cohort (13% vs 30%, p<0.001), while no difference was found in terms of 3-years chronic GVHD. 1-year NRM did not differ among the two groups (p=0.365), while PK-TBF was significantly more advantageous relative to no-PK TBF in terms of 3-years GRFS: 49% vs 34% (p=0.019).

Conclusion PK-guided TBF results in improved outcomes relative to no-PK TBF in terms of CIR, acute GVHD, OS, PFS. These resulted in a more favorable GRFS in patients treated with PK relative to no PK TBF. PK-TBF represents a promising platform, even for older patients, ensuring higher efficacy while preserving reduced toxicity.

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2025
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