Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy

Takahashi, Takuto; Scheibner, Aileen; Cao, Qing; Pearson, Rachael A.; Sanghavi, Kinjal; Weisdorf, Daniel J.; Brunstein, Claudio G.; Rogosheske, John; Bachanová, Veronika; Warlick, Erica D.; Wiseman, Anthony; Jacobson, Pamala A.

doi:10.1016/j.jtct.2021.05.013

Cited by 3 publications

(5 citation statements)

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“…Although the exposure‐response analysis of PM is limited, our previous study demonstrated that patients with PM AUC 0‐8h >34235 ng • h/mL had greater nonrelapse mortality (≈>20% from the median value). 8 It is not known why these patients had a higher PM AUC 0‐8h, but it appears that renal function is 1 reason that may contribute slightly to a higher PM exposure. In the cyclophosphamide package insert, 28 elevated exposures in severe renal failure patients are noted with the recommendation to monitor signs and symptoms of toxicity.…”

Section: Discussionmentioning

confidence: 96%

“…Of note, due to nonlinearity of the system, CrCL has only a small influence on PM exposure at early time points (AUC 0‐8h ) as it is driven mainly by the formation and distribution of PM rather than elimination (Figure S3). Although the exposure‐response analysis of PM is limited, our previous study demonstrated that patients with PM AUC 0‐8h >34235 ng • h/mL had greater nonrelapse mortality (≈>20% from the median value) 8 . It is not known why these patients had a higher PM AUC 0‐8h, but it appears that renal function is 1 reason that may contribute slightly to a higher PM exposure.…”

Section: Discussionmentioning

confidence: 99%

“…This is a single‐center, observational PK study of PM in 110 adult patients undergoing allogeneic HCT with a conditioning regimen containing a single‐dose cyclophosphamide, fludarabine, and TBI at the University of Minnesota Hospital. Details of the clinical study were published previously 8 . Patients with high‐risk hematologic malignancy with adequate organ function were eligible (transaminases <5‐fold of the upper limit of normal, total bilirubin <2.5 mg/dL, left ventricular ejection fraction >40%).…”

Section: Methodsmentioning

confidence: 99%

“…Details of the clinical study were published previously. 8 Patients with high‐risk hematologic malignancy with adequate organ function were eligible (transaminases <5‐fold of the upper limit of normal, total bilirubin <2.5 mg/dL, left ventricular ejection fraction >40%). Adequate renal function was defined by serum creatinine ≤2.0 mg/dL and estimated CrCL ≥40 mL/min/1.73 m 2 .…”

Section: Methodsmentioning

confidence: 99%

“… 7 These previous studies did not assess the effects of PM, and as the final active metabolite, PM is expected to represent a good surrogate for cyclophosphamide safety and efficacy. To that end, our group recently studied PM exposure‐response relationships and showed that patients with high PM exposure had greater nonrelapse mortality and lower overall survival in HCT, 8 suggesting that PM may be a good measure of HCT outcomes. Should PM exposure be linked similarly to efficacy or toxicity in additional studies, a better understanding of the cyclophosphamide dose‐patient variables–PM exposure relationships is important for improved dosing.…”

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confidence: 99%

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Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis

Jaber

Takahashi

Kirstein

et al. 2022

The Journal of Clinical Pharma

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Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed-effects modeling. Mixed linear and nonlinear elimination pathways were required to adequately describe the disposition of PM. Creatinine clearance (CrCL) was incorporated as a covariate associated with first-order elimination, representing renal clearance (Cl R ) of PM. For a 70-kg patient, Cl R was 14.9 L/h, Volume of distribution was 525 L, maximum rate was 81.2 mg/h, and the concentration to achieve 50% of maximum rate was 0.51 mg/L. We conducted simulations to explore the impact of CrCL as a measure of renal function and observed that when CrCL decreases from 120 to 40 mL/min, PM area under the plasma concentration-time curve (AUC) from time 0 to 8 hours and AUC increases by 9.2% and 80.9% on average after a single dose, respectively. Our data suggest that renal function has limited influence on PM exposure during the first 8 hours after dosing but has a large impact on the total exposure. Dose adjustment of cyclophosphamide may not be necessary in hematopoietic cell transplant recipients with moderate to severe kidney dysfunction to attain targeted exposures based on AUC from time 0 to 8 hours. However, dose reduction may be necessary if demonstrated at some future time that total AUC is a better surrogate for safety or toxicity.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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