In this study, using Japanese registry data, we compared the outcomes of transplantation with different Flu doses in the FB and FM regimens. These regimens are widely used as RIC or RTC regimens for unrelated bone marrow transplantation. In this registry study, a significant difference in the proportion of patients receiving high-dose Flu was observed between the FB and FM groups. Our findings indicate that high-dose Flu was associated with favorable outcomes, particularly a lower relapse rate than low-dose Flu, for unrelated bone marrow transplantation in the FB group. However, this association was not observed in the FM group.
Flu is a well-known, potent immunosuppressive agent that plays a central role in RIC and RTC regimens. In terms of the conditioning regimen with FB, the first retrospective study, conducted by Slavin et al., demonstrated the efficacy of Flu (180 mg/m2) combined with busulfan in matched-related peripheral blood stem cell transplantation [3]. Many reports have been published since then, but Flu doses vary between 120 and 250 mg/m2 [3, 12–18]. Surprisingly, there are no reports specifically addressing Flu doses or comparing the effects of different Flu doses in the setting of unrelated bone marrow transplantation. However, Geddes et al. conducted a study on the effects of high busulfan concentrations in combination with high-dose Flu (250 mg/m2) and found no apparent increase in side effects [15]. In terms of the conditioning regimen with FM, Giralt et al. reported the results of initial studies using Flu (125 mg/m2) in combination with melphalan for a variety of hematologic malignancies [27]. In other subsequent reports, the Flu doses in the FM regimen vary from 100 to 160 mg/m2 [19–21]. Although there are many reports on different Flu doses, a Flu dose of 180 mg/m2 has been more commonly used in the FB regimen, and Flu doses of 125–150 mg/m2 have been used in the FM regimen, which are lower than those used in the FB regimen. In studies comparing FB to FM regimens, it is common for the FM group to receive a lower Flu dose [28–30]. Since none of the reports mention Flu doses, these dose decisions are probably influenced by the initial reports [3, 27]. In our study, as in previous reports, many cases in the FB group received a Flu dose of 180 mg/m2, while many cases in the FM group received a Flu dose of 125 mg/m2.
In our study, we observed a significantly lower recurrence rate in the Flu (180 mg/m2) group of the FB group, but no difference was found in the FM group. However, the risk of relapse varies with the hematologic diagnosis, and this should be considered when interpreting these results. In the FB group, there was no significant difference in relapse rate based on the Flu dose across different diseases. This may be due to the small number of cases and differences in patient backgrounds. Therefore, further accumulation, and investigation of cases are necessary in the future.
Several reports have been conducted to investigate the relationship between F-Ara-A concentrations (the active component of fludarabine in the plasma) and transplantation outcomes. Flu dosing is currently based on body surface area, which can result in variable exposure to the drug. Langenhorst et al. conducted a pharmacokinetic-pharmacodynamic analysis on patients undergoing HSCT with Flu as part of a myeloablative conditioning regimen [31]. They found that event-free survival was lower in the Flu-overexposed group, owing to higher NRM associated with impaired immune reconstitution. Additionally, the risk of NRM, and graft failure was increased in the Flu-underexposed group. However, no association with relapse was found. In other reports, no significant associations were found between the degree of Flu exposure and relapse or survival in adult and pediatric HSCT [32, 33]. However, in a study of pediatric patients with hematologic diseases, maintaining adequate Flu blood concentration resulted in high disease-free survival without increasing transplant-related mortality [34]. In our study, Flu blood concentration was not assessed, but a high Flu dose was associated with improved OS due to a lower relapse rate, with no apparent increase in NRM. While maintaining an adequate Flu blood concentration may lead to favorable outcomes, the concentration can fluctuate due to various factors such as renal function, age, and body weight. Therefore, further analysis is needed to determine individualized Flu dosing for each case in the future.
Previous reports have indicated that the FB regimen had a higher proportion of early mixed donor chimerism than the FM regimen [35, 36]. Although our study did not assess chimerism, we believe that the reason for the significantly different relapse rate in the FB group but not in the FM group is the different timing of achieving complete chimerism in the FM and FB groups. For instance, the FM group may experience an early transition to complete chimerism, which may reduce relapse rates associated with low-dose Flu.
This retrospective cohort study has some limitations. First, the proportions of patients receiving high-dose Flu differed significantly between the FB and FM groups, with more patients receiving HFB in the FB group and more patients receiving LFM in the FM group. Therefore, a direct comparison of the results between these two groups is not possible. Second, the heterogeneous patient backgrounds, such as disease type, PS, and total body irradiation use, may have introduced statistical bias, although we attempted to adjust for this by conducting multivariate analyses. Third, depending on the dose of busulfan or melphalan, there may be interactions with different effects of the dose of Flu, which we have not been able to assess. Finally, our registry did not collect detailed information such as Flu pharmacokinetic data or chimerism. If this information had been available, it would have been possible to assess the role of different Flu doses in HSCT in more detail.
In conclusion, our retrospective data analysis revealed that high-dose Flu was associated with a favorable outcome in the FB group but not in the FM group. Prospective studies and further investigation are needed to elucidate the benefit of high-dose Flu in the setting of the FB regimen.