Introduction: In a previous report, we found that post-transplant clinical outcomes were not significantly different between MAC (BuCy, CyTBI) and RIC (FluBu2TBI400) groups in AML CR1 with pre-transplant low WT1 expression. Based on this result, we expanded the use of conditioning regimen with reduced dose intensity for patients achieving deep response by minimal residual disease (MRD) assessment with available assays. FluBu3 regimen, consisting of fludarabine for 5 days (30mg/m2/day, D-6 to D-2) and busulfan for 3 days (3.2mg/kg/day, D-5 to D-3), was chosen and applied as reduced toxicity conditioning (RTC) in our institution since Jan 2017.

Method: In this analysis, we compared MAC and RTC regimens; BuCy (busulfan 3.2 mg/kg/day for 4 days from D-7 to D-4 and cyclophosphamide 60 mg/kg/day for 2 days from D-3 to D-2) and FluBu3 protocols were used as MAC and RTC regimen, respectively. The inclusion criteria were set as follows: (1) adult (age ≥ 18 years) AML patients who were registered in a prospective cohort study; (2) receiving first allogeneic hematopoietic stem cell transplantation (HSCT) in CR1 between Aug 2017 and Nov 2021; (3) MRD negative at pre-transplant; (4) transplantation from either HLA-matched (8/8) sibling donor (MSD), matched unrelated donor (MUD) or 1-locus mismatched (7/8) unrelated donor (MMUD); (5) the use of either BuCy or FluBu3 conditioning. MRD negativity was defined by the absence of abnormalities in the following order; (i) <3 log reduction in RUNX1-RUNX1T1 and CBFB-MYH11, (ii) <4 log reduction of NPM1 level from diagnosis, and (iii) pre-transplant WT1 levels ≥ 250 copies for RUNX1-RUNX1T1, CBFB-MYH11, or NPM1 mutation negative AML. Peripheral blood was used as the source of stem cells in all patients, and the data was analyzed based on information available as of Jun 2022.

Results: A total of 124 patients met the inclusion criteria, and 78 (62.9%) and 46 (37.1%) patients received BuCy and FluBu3 conditioning, respectively. The median age was 45 years and the patients with intermediate cytogenetics comprised the majority (71.8%). By the donor type, 64 (51.6%), 48 (38.7%) and 12 (9.7%) patients underwent MSD, MUD and MMUD transplantation. Between the two conditioning groups, patients receiving FluBu3 were older (median 39.5 vs 53 years, p<0.001) and significantly more patients in the FluBu3 group had received ATG (37.9% vs 93.5%, p<0.001). In each of the BuCy and FluBu3 groups, after median follow up of 39.5 and 53 months (p<0.001), the 2-year overall survival (OS) of 78.3% and 84.5% (p=0.358), relapse free survival (RFS) of 78.0% and 76.3% (p=0.806), cumulative incidence of relapse (CIR) of 7.7% and 21.5% (p=0.074) and non-relapse mortality (NRM) of 14.3% and 2.2% (p=0.0324) were observed. In addition, the probabilities of grade II-IV acute graft versus host disease (aGVHD) and cGVHD of moderated to severe at 2-year for BuCy and FluBu3 were 46.2% and 39.2% (p=0.306), and 59.5% and 36.0% (p=0.008), respectively. At the time of data cut-off, relapse was the main cause of HSCT failure in FluBu3 group (n=8) while NRM contributes most to HSCT failure in BuCy group (n=11). Six of 8 relapsed patients receiving FluBu3, compared to 1 out of 6 in BuCy group, had high-risk features of either poor cytogenetics or FLT3-ITD mutation. The majority of NRM in the BuCy group, 8 out of 11 cases, was due to GVHD and 4 of them received transplantation from MMUD.

Conclusion: Among the AML patients in MRD negative CR1, the FluBu3 RTC regimen showed a comparable post-HSCT outcomes to a BuCy conditioing in terms of similar OS and RFS, while associated with significant reduced NRM that was offset by trend towards higher risk of relapse.

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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