Department of Stem Cell Transplantation, University Medical Center Eppendorf, University of Hamburg, Hamburg, Germany.
Hospital Pharmacy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Eur J Haematol. 2023 Feb;110(2):188-197. doi: 10.1111/ejh.13893. Epub 2022 Dec 1.
Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. Eighty-seven patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. Thirty-two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n = 18/25 (72%); decreased: n = 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2%-19% vs. 35%, 23%-49% p = 0.02), improved 3-year leukemia-free survival (LFS) (78%, 54%-91% vs. 55%, 40%-70% p = 0.009) and - overall survival (OS) (82%, 60%-93% vs. 69%, 54%-81% p = 0.05) after individualized compared to fixed Bu. Non-relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p = 0.044), LFS (HR 3.6, p = 0.018) and relapses (HR 3.6, p = 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p = 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity.
移植前微小残留病 (MRD) 对急性髓系白血病 (AML) 移植后的复发风险有负面影响。通过计算曲线下面积 (AUC) 来进行治疗药物监测，以优化白消安 (Bu) 的暴露。在这里，我们比较了在达到异体移植前完全缓解的中危 AML 患者中，个体化 Bu 剂量与固定 Bu 剂量在移植后结局方面的差异，重点关注移植前流式细胞术-MRD。纳入了 87 例（中位数年龄为 56 岁）中危 AML 且移植前流式细胞术-MRD（“不同于正常”）阳性的患者。32 例患者接受个体化 Bu；54 例患者接受固定剂量 Bu。在 25/32 例患者中调整了个体化剂量：增加，n=18/25（72%）；减少：n=7/25（28%）。在中位随访 27 个月后，我们观察到较低的 3 年复发率（6%，2%-19%vs.35%，23%-49%，p=0.02）、改善的 3 年无白血病生存率（LFS）（78%，54%-91%vs.55%，40%-70%，p=0.009）和总生存率（OS）（82%，60%-93%vs.69%，54%-81%，p=0.05），与固定 Bu 相比，个体化 Bu 具有优势。非复发死亡率（NRM）和急性移植物抗宿主病（GvHD）无差异。多变量分析显示，固定 Bu 对 OS（危险比 [HR]4.6，p=0.044）、LFS（HR3.6，p=0.018）和复发（HR3.6，p=0.033）均有不利影响。固定 Bu 也对移植前 MRD 阳性患者的 LFS（3.6，1.1-12.6，p=0.041）有不利影响。在达到完全缓解的中危 AML 患者中，基于 AUC 的个体化 Bu 与较低的复发率相关，可能克服移植前 MRD 阳性。
