Predictors of increased melphalan exposure correlate with overall survival, nonrelapse mortality, and toxicities in patients undergoing reduced-intensity allogeneic stem cell transplantation with fludarabine and melphalan

Abstract

The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m2 (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) ( p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality ( p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival ( p = 0.017). In patients with a lower Hb, the median duration of hospitalization ( p = 0.02) and the mean duration of diarrhea ( p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization ( p = 0.06) and the mean duration of diarrhea ( p = 0.0009) longer, and the rate of infection was higher ( p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.

An ISCT Stem Cell Engineering Committee Position Statement on Immune Reconstitution: the importance of predictable and modifiable milestones of immune reconstitution to transplant outcomes

“…More recent work has demonstrated that the model used for these calculations has profound effects on outcomes of interest including freedom from infectious complications and emphasizes the importance of personalized dosing [63]. Targeted dosing of other agents used in cytoreduction including melphalan [64] and fludarabine [65] can also improve HCT outcomes with evidence that over-exposure to fludarabine also impairs post-HCT IR [65]. Current studies are assessing the role of targeted peri-HCT exposure to fludarabine and subsequent immune reconstitution.…”