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Fludarabine Metabolite Level on Day Zero Does Not Affect Outcomes of Hematopoietic Cell Transplantation in Patients with Normal Renal Function

Track: Poster Abstracts
Saturday, March 1, 2014, 6:45 PM-7:45 PM
Longhorn Hall E (Exhibit Level 1) (Gaylord Texan)
Cameron D. Griffiths, MD , Internal Medicine, Alberta Health Services, Calgary, AB, Canada
Ella S.M Ng, MSc , Alberta Health Services, Calgary, AB, Canada
Bill Kangarloo, MSc. , Alberta Health Services, Calgary, AB, Canada
Tyler S. Williamson, PhD , Queen's University, Kingston, ON, Canada
Reanne Booker , Bone Marrow Transplant, Tom Baker Cancer Centre, Calgary, AB, Canada
Ping Yue, MD , Tom Baker Cancer Center, Calgary, AB, Canada
Peter Raymond Duggan, MD , Blood and Bone Marrow Transplant Program, Tom Baker Cancer Centre/Foothills Hospital, Calgary, AB, Canada
Mary Lynn Savoie, MD, FRCPC , Blood and Bone Marrow Transplant Program, Tom Baker Cancer Centre/Foothills Hospital, Calgary, AB, Canada
Chris Brown, MD , Blood and Bone Marrow Transplant Program, Tom Baker Cancer Centre/Foothills Hospital, Calgary, AB, Canada
Andrew Daly , Blood and Bone Marrow Transplant Program, Tom Baker Cancer Centre/Foothills Hospital, Calgary, AB, Canada
James A Russell, MA, MB , Blood and Bone Marrow Transplant Program, Tom Baker Cancer Centre/Foothills Hospital, Calgary, AB, Canada
Jan Storek, MD, PhD , Tom Baker Cancer Centre/Foothills Hospital, Calgary, AB, Canada

Background

Fludarabine is a common constituent of conditioning for hematopoietic cell transplantation (HCT). It is a prodrug that is dephosphorylated in plasma to its measurable metabolite, F-ara-A, which after intracellular rephosphorylation interferes with DNA replication, transcription and translation, and induces apoptosis.

Due to variable renal clearance, F-ara-A levels on day 0 are variable. The clinical relevance of the F-ara-A persisting in plasma is unknown. The goal of this study was to assess the relationship between F-ara-A levels on day 0 and clinical outcomes including GVHD, infections, relapse and death.

Patients and Methods

We included 166 consecutive patients undergoing first allogeneic transplantation of filgrastim-mobilized blood stem cells for a hematologic malignancy between December 2008 and 2012.  Conditioning was myeloablative, and included fludarabine (50 mg/m2 daily from days -6 to -2), busulfan and antithymocyte globulin. Additional GVHD prophylaxis included methotrexate and cyclosporine.  The interval between the last fludarabine dose and graft infusion was 48-72 hours. F-ara-A serum levels were measured using mass spectrometry.

Results

In univariate analyses, there was no difference in median F-ara-A levels between patients who did vs did not develop acute GVHD grade 2-4, acute GVHD grade 3-4, any chronic GVHD, chronic GVHD needing systemic therapy (NST), CMV reactivation above our threshold for preemptive therapy (25,000 IU/mL), post-transplant lymphoproliferative disorder (PTLD), relapse, death or non-relapse death (Figure 1).

In multivariate analyses, there was no difference in the likelihood of developing any one of the outcomes between patients whose F-ara-A level was above vs below median (14 ng/mL). We also assessed for differences in the likelihood of developing each outcome between patients with levels in the fourth quartile (21-104 ng/mL) vs the first quartile (1-9 ng/mL). Again, in this analysis, there was no difference for any outcome.

We also noted a weak correlation between F-ara-A levels on day 0 and the day of neutrophil engraftment (r=0.16, p=0.04), and a trend towards more bacterial infections in patients with F-ara-A levels in the fourth vs first quartile.

Discussion

The results suggest that there is no or minimal impact of day 0 F-ara-A levels on clinical outcomes. This may be due to the fact that F-ara-A levels on day 0 were relatively low (1-104 ng/mL, median 14 ng/mL) compared to levels 1-4 hours after fludarabine infusion (~1,000 ng/mL).

Conclusion

Day 0 F-ara-A levels are highly variable (1-104 ng/mL), likely due to variable renal function. Given that we found no association between the day 0 levels and clinical outcomes we do not support delaying graft infusion until F-ara-A level has dropped below a certain level, as long as the last fludarabine dose is given within 48 hours of graft infusion and to patients with normal renal function.

Disclosures:
Nothing To Disclose
See more of: Poster Session 2: Allogeneic Transplants
See more of: Poster Abstracts
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