Influence of Fludarabine Pharmacokinetics on Outcome of Allogeneic Stem Cell Transplantation with Fludarabine-Busulfan Conditioning
Bibliographic record
Abstract
Abstract Introduction Precise targeting of Busulfan dose has resulted in improved transplant outcomes following myeloablative conditioning with Fludarabine plus Busulfan (Flu-Bu). However, the impact of Fludarabine pharmacokinetics on outcomes in allogeneic stem cell transplantation (SCT) following myeloablative conditioning remains undefined. Methods A retrospective single-centre analysis was performed to evaluate the clinical outcomes of 88 patients who received Flu-Bu based conditioning. Patients received Flu (50mg/m2 days-6 to -2), Bu (3.2mg/kg days-5 to -2), and Total Body Irradiation (400 cGy in two doses on day-1). Busulfan dosing was adjusted to achieve a total exposure of 3750 μmol·min/L. Levels of the Fludarabine metabolite 9βD-arabinofuranosyl-2-fluoroadenosine were determined by high performance liquid chromatography-tandem mass spectrometry. Fludarabine exposure, expressed as Fludarabine area under the concentration-time curve (AUC), was calculated on patient blood samples collected on day-5. Results Median age of the 88 patients was 49 (range 18-65) years, and median creatinine clearance was 120.5mL/min (range 48-305mL/min). The most common transplanted hematologic malignancies included AML (31%), ALL (20%), and MDS (10%). 32 (36%) received their transplants from HLA-compatible siblings, and 56 (64%) from unrelated donors. Median plasma AUC was 9.038μg·h/mL (range 2.429 - 66.655μg·h/mL). When comparing patients with lower Flu exposure <9.000μg·h/mL versus those with higher Flu exposure >9.000μg·h/mL, there was no significant difference in grade II-IV acute Graft versus Host Disease (aGvHD; 25% versus 32%, p=0.27) or grade III-IV aGvHD (11% versus 14%, p=0.52). Furthermore, there was no difference in average days to engraftment (13.8 versus 13.9, 95% CI 13.01 - 14.72, p=0.77), or average number of infections in 1-year post transplant (2.3 versus 2.5, 95% CI 1.68 - 3.30, p=0.68). Transplant related mortality (TRM) at 100 days was not improved (7.0% versus 11.4%, p= 0.52) with AUC <9.000μg·h/mL. Progression free survival at 3 years with lower Flu exposure <9.000μg·h/mL was 68% (95%CI 53 - 79) compared to higher Flu exposure >9.000μg·h/mL at 59% (95% CI 45-73, p=0.70). Finally, there was no difference in overall survival (OS) at 12 months (Figure 1.0) in patients with an AUC <9.000μg·h/mL (73%, 95% CI 57-83) versus those with AUC >9.000μg·h/mL (73%, 95% CI 55-83, p-value 0.99). Conclusion In the setting of normal renal function, we have demonstrated that Fludarabine pharmacokinetics does not effect clinical outcomes in myeloablative allogeneic SCT. These data support no role for therapeutic dose monitoring and dose adjustment with Fludarabine in myeloablative conditioning regiments. Figure 1. Overall survival for patients 12 months after myeloablative SCT with Fludarabine AUC <9.000μg·h/mL compared to patients with Fludarabine AUC >9.000μg·h/mL. Figure 1. Overall survival for patients 12 months after myeloablative SCT with Fludarabine AUC <9.000μg·h/mL compared to patients with Fludarabine AUC >9.000μg·h/mL. Disclosures Off Label Use: Fludarabine in the use of myeloablative conditioning for allogeneic stem cell transplantation..
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".