Fludarabine metabolite level on day zero does not affect outcomes of hematopoietic cell transplantation in patients with normal renal function

Griffiths, Cameron; Ng, Ella S.M.; Kangarloo, Shahbal B.; Williamson, Tyler; Chaudhry, M. Ahsan; Booker, Reanne; Duggan, Peter; Yue, Ping; Savoie, Lynn; Brown, Christopher B.; Cox-Kennett, Nanette; Russell, James A.; Daly, Andrew; Storek, Jan

doi:10.1038/bmt.2013.234

Cited by 2 publications

(3 citation statements)

References 4 publications

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“…(16) A letter to the editor reported on 166 HCT recipients receiving fludarabine 50mg/m 2 days -6 to -2 and busulfan with or without TBI. (12) F-ara-A concentrations on day of HCT were not associated with risk of acute GVHD, CMV reactivation, risk of relapse, or death due to any cause. These data may suggest that when fludarabine is combined with busulfan or given in a conditioning regimen using four or fewer doses of fludarabine the exposure response relationships may be modest.…”

Section: Discussionmentioning

confidence: 84%

Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning

Sanghavi

Wiseman

Kirstein

et al. 2016

Translational Research

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Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of non-relapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft vs host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/hr (p<0.01) and area under the curve (AUCpred)>6.00 μg*hr/mL (p=0.01). A lower Clpred was also associated with more NRM at month 6 (p=0.01) and trended towards significance at 12 months (p=0.05). In multivariate analysis, low fludarabine clearance trended towards higher risk of acute GVHD (p=0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing in overweight individuals and those with altered kidney function.

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Section: Discussionmentioning

confidence: 84%

Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning

Sanghavi

Wiseman

Kirstein

et al. 2016

Translational Research

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“…Day 0 F‐ara‐A concentrations were highly variable (1–104 ng/mL), attributed to a variable, although normal, renal function. 27 However, these results have not been validated and need future research. Antithymocyte globulin (ATG) can be used in conditioning regimens as an in vivo form of T‐cell depletion, potentially decreasing the risks of graft rejection or the development of GVHD.…”

Section: Discussionmentioning

confidence: 94%

“…After fludarabine administration, 9‐β‐D‐arabinofuranosyl‐2‐fluoroadenine or 2‐fluoro‐ara‐A (F‐ara‐A) concentrations on day 0 were not associated with clinical outcomes after HCT. Day 0 F‐ara‐A concentrations were highly variable (1–104 ng/mL), attributed to a variable, although normal, renal function 27 . However, these results have not been validated and need future research.…”

Section: Discussionmentioning

confidence: 96%

The presence of busulfan metabolites and pharmacometabolomics in plasma drawn immediately before allograft infusion in hematopoietic cell transplant recipients

McCune,

Navarro,

Risler

et al. 2023

Clinical Translational Sci

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Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ‐glutamyldehydroalanylglycine (EdAG), which is too unstable to be quantitated in vivo. We sought to evaluate if pregraft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites’ and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) patients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non‐relapse mortality, and neutrophil nadir. In pregraft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: 1. The presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1‐oxide, sulfolane, and 3‐hydroxysulfolane (N=124); 2. EMCs using a global metabolomics assay (N=77). 3. The association of the busulfan metabolites and the EMCs with clinical outcomes. In the pregraft samples, busulfan and THT+ could not be detected. Tetrahydrothiophene 1‐oxide, sulfolane, and 3‐hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pregraft samples; their concentrations were not associated with clinical outcomes. Four pregraft EMCs were statistically significantly associated with the neutrophil nadir. The pregraft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients’ plasma immediately before allograft infusion; the neutrophil nadir is associated with pregraft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfans’ metabolites and EMCs in the pregraft plasma from allogeneic HCT recipients.

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Fludarabine metabolite level on day zero does not affect outcomes of hematopoietic cell transplantation in patients with normal renal function

Cited by 2 publications

References 4 publications

Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning

Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning

The presence of busulfan metabolites and pharmacometabolomics in plasma drawn immediately before allograft infusion in hematopoietic cell transplant recipients

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