Individualized busulfan dosing improves outcomes compared to fixed dose administration in pre-transplant MRD positive AML patients with intermediate risk undergoing allogeneic stem cell transplantation in CR.

Klyuchnikov, Evgeny; Langebrake, Claudia; Badbaran, Anita; Dadkhah, Adrin; Massoud, Radwan; Freiberger, Petra; Ayuk, Francis; Janson, Dietlinde; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus (2023). Individualized busulfan dosing improves outcomes compared to fixed dose administration in pre-transplant MRD positive AML patients with intermediate risk undergoing allogeneic stem cell transplantation in CR. European journal of haematology, 110(2), pp. 188-197. Wiley 10.1111/ejh.13893

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Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in AML. Therapeutic drug monitoring by calculating area-under-the-curve (AUC) was developed to optimize busulfan 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. 87 patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. 32 patients received individualized busulfan; 54 fixed dosage. 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 LFS (78%, 54-91% vs 55%, 40-70% p = 0.009) and -OS (82%, 60-93% vs 69%, 54-81% p = 0.05) after individualized compared to fixed Bu. NRM and acute GvHD were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (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.

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