Bone Marrow Transplantation (2014) 49, 589–591 & 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Fludarabine metabolite level on day zero does not affect outcomes of hematopoietic cell transplantation in patients with normal renal function graft-vs-leukemia reaction) or decrease the likelihood of GVHD. In addition, a high day 0 level may be a surrogate for a high area under the time–concentration curve (AUC), which could be associated with decreased likelihood of relapse or increased likelihood of death due to organ toxicity. The goal of this study was to assess the relationship between day 0 F-ara-A levels and clinical outcomes. Conditioning of all patients included fludarabine, 50 mg/m2 daily from day 6 to day 2. For additional patient characteristics and methods, see Supplementary Material online. As expected, there was an inverse correlation between the day 0 F-ara-A levels and creatinine clearance (estimated with Cockroft–Gault equation using the average of daily creatinine determinations from day 6 to day 0; r ¼ 0.42, Po0.01, Spearman correlation). We found no cases of transplant-related neurotoxicity attributable to conditioning. In univariate analyses, there was no difference in median F-ara-A levels between patients who did and those who did not
10
10
10
1
1
1
Any cGVHD
10
10
10
1
1
1 N
Ye s
N
Ye s
PTLD 100
10
10
10
1
1
1 Ye s
N
Ye s
N
Relapse
o
100
o
100
Death
o
CMV reactivation
N
N
o
100
o
100
o
100
“Extensive”cGVHD
Ye s
Ye s
N
N
Ye s
aGVHD (gr. 3-4)
aGVHD (gr. 2-4)
F-Ara-A (ng/mL)
N o
100
o
100
o
100
Ye s
Fludarabine, an immunosuppressive and cytotoxic purine analog, is a common constituent of conditioning for hematopoietic cell transplantation (HCT). Fludarabine (F-ara-AMP) is a prodrug that is dephosphorylated in plasma to 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A). On entry into a cell, F-ara-A is phosphorylated to F-ara-ATP, which interferes with DNA replication, transcription and translation, and induces apoptosis.1,2 Owing to variable renal clearance,3 F-ara-A levels on day 0 (immediately before graft infusion) may be variable. The clinical relevance of the F-ara-A persisting in plasma on day 0 is unknown. High day 0 levels may negatively impact the hematopoietic stem cells or lymphocytes infused with the graft, which could increase the likelihood of infections or relapse (by abrogating a
Ye s
Bone Marrow Transplantation (2014) 49, 589–591; doi:10.1038/ bmt.2013.234; published online 27 January 2014
Non-relapse death
Figure 1. No significant difference in day 0 F-ara-A levels between patients with and those without GVHD, CMV reactivation above our threshold for preemptive antiviral therapy (25 000 IU/mL plasma), post-transplant lymphoproliferative disorder (PTLD), relapse, non-relapse death or death due to any cause. For each clinical outcome, P was 40.05 (range, 0.22–0.78). Mann–Whitney–Wilcoxon test was used. ‘Extensive’ cGVHD means chronic GVHD needing systemic therapy.
Letter to the Editor
590 develop acute GVHD (aGVHD) grade 2–4, aGVHD grade 3–4, any chronic GVHD, ‘extensive’ chronic GVHD (needing systemic therapy), CMV reactivation, post-transplant lymphoproliferative disorder, relapse, death or non-relapse death (Figure 1 and Supplementary Table 2). There was also no significant association between the F-ara-A levels and the rates of infections of all categories, except for bacterial infections and definite infections (defined as described Hoegh-Petersen et al.4) (Supplementary Table 3). 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 and those whose level was below the median of 14 ng/mL (Table 1, Supplementary Figure 1 and Supplementary Table 4). Given the clustering of most F-ara-A levels near the median (Figure 1), to assess for differences between patients with extreme levels we analyzed whether there was a difference in the likelihood of developing each outcome between patients with levels in the fourth quartile (21–104 ng/mL) and those with levels in the first quartile (1–9 ng/mL). Again, in this analysis, there was no significant difference for any outcome (Table 1 and Supplementary Figure 1). However, there was a trend toward more bacterial infections in patients with high F-ara-A levels (Table 1). As patients with high F-ara-A level experienced later neutrophil engraftment (Supplementary Table 3), we hypothesized that this caused the trend toward more bacterial infections. Thus, we compared the median day of engraftment between patients who did not and those who did develop X1 bacterial infection(s) (between day 0 and 83). We found no difference (median day 14 vs 14, P ¼ 0.55, Mann–Whitney– Wilcoxon test). We also tested for the correlation between the
day of neutrophil engraftment and the rate of day 0–83 bacterial infections, and found no correlation (Spearman’s r ¼ 0.0136, P ¼ 0.8619). Thus, the reason for the trend toward more bacterial infections in patients with higher F-ara-A levels remains unexplained. The results suggest that, within the power of this study, there is no significant impact of day 0 F-ara-A level on clinical outcomes. This may be due to the fact that even the patients with the highest quartile had relatively low F-ara-A levels (21–104 ng/mL), compared with B1000 ng/mL at 1–4 h after infusion of 30 mg/m2 of fludarabine.2 This is the first published analysis of the effect of F-ara-A day 0 level on clinical outcomes after HCT. The closest published study is that of Long-Boyle et al.,3 which demonstrated a lower risk of grade 2–4 aGVHD and an increased risk of non-relapse and overall mortality in patients with high F-ara-A AUC. Possible reasons for the apparently discrepant results between Long-Boyle’s and our studies are: (1) total exposure over a 5-day period from day 6 to 2 (AUC) was measured in the Long-Boyle’s study as opposed to day 0 levels in our study (Correlation between the AUC and the day 0 level may be imperfect, for example, because the time between the last fludarabine dose and graft infusion is variable (at our institution 48–72 h after the last fludarabine dose.); (2) conditioning in Long-Boyle’s study consisted of CY þ fludarabine þ TBI±ATG compared with BU þ fludarabine þ ATG±TBI in our study (GVHD prophylaxis included mycophenolate mofetil from day 3 plus cyclosporine from day 3 in LongBoyle’s study vs MTX from day þ 1 plus cyclosporine from day 1 in our study. Thus, different drug–drug interactions may have a
Table 1. Multivariate analysis of association between high fludarabine levels and outcomes, using log-binomial regression (for one-time outcomes)a, or Poisson regression (for infections)b Outcome
Above vs below median RR (95% CI)
aGVHD (grade 2–4) aGVHD (grade 3–4) Any cGVHD ‘Extensive cGVHD’ CMV reactivation PTLD Relapse Non-relapse death Death due to any cause
0.90 1.06 1.51 1.37 1.02 1.30 0.72 1.45 1.02
(0.53–1.62) (0.42–2.66) (0.54–4.21) (0.81–2.32) (0.61–1.71) (0.39–3.33) (0.40–1.29) (0.56–3.76) (0.47–2.21)
IRR (95% CI) Any infection Definite infection Viral infection Bacterial infection Fungal infection Any severe infection Definite severe infection
1.15 1.21 1.06 1.36 0.76 0.94 0.92
(0.88–1.50) (0.92–1.61) (0.73–1.54) (0.89–2.10) (0.20–2.88) (0.64–1.37) (0.62–1.36)
Fourth vs first quartile P-value 0.73 0.90 0.43 0.24 0.95 0.67 0.27 0.44 0.95 P-value 0.30 0.18 0.77 0.15 0.69 0.73 0.68
RR (95% CI) 0.77 0.71 0.72 1.21 1.16 0.97 0.55 1.19 0.85
(0.36–1.65) (0.25–2.06) (0.40–1.30) (0.62–2.37) (0.61–2.19) (0.24–2.95) (0.20–1.50) (0.35–3.00) (0.31–2.34)
IRR (95% CI) 1.27 1.35 1.24 1.59 0.64 1.03 0.98
(0.89–1.79) (0.30–1.96) (0.76–2.03) (0.90–2.81) (0.11–3.87) (0.64–1.68) (0.60–1.61)
P-value 0.50 0.53 0.28 0.58 0.65 0.97 0.24 0.78 0.75 P-value 0.19 0.11 0.39 0.10 0.63 0.88 0.95
Abbreviations: CI ¼ confidence interval; IRR ¼ incidence rate ratio of day 0–83 infections among patients with high vs low F-ara-A level; NRD ¼ non-relapse death; PTLD ¼ post-transplant lymphoproliferative disorder; RR ¼ risk ratio of outcome among patients with high vs low F-ara-A level, that is, above vs below median in the ‘above vs below median’ analysis, and above 75th percentile vs under 25th percentile in the ‘fourth vs first quartile’ analysis. High fludarabine levels were defined as levels above median (in the above vs below median analysis) or above 75th percentile (in the fourth vs first quartile analysis). a Multivariate analysis to determine whether patients with high F-ara-A level had a higher likelihood of developing the outcome (RR 41) or lower likelihood of the outcome (RRo1). Covariates considered were (1) for acute and chronic GVHD, donor type (HLA-matched sibling vs other), gender combination (male/male vs other) and patient age (above vs below 45 years); (2) for CMV reactivation above our institutional threshold for preemptive antiviral therapy (25 000 IU/mL plasma), CMV IgG serostatus pretransplant ( þ / þ , þ / , / þ , / ) and presence or absence of significant GVHD; (3) for PTLD, donor type, patient age, EBV serostatus pretransplant and presence or absence of significant GVHD (grade 2–4 acute GVHD or chronic GVHD needing systemic therapy) before PTLD onset; (4) for relapse, disease risk index (low-intermediate vs high-very high), donor type, gender combination and patient age; and (5) for non-relapse death and for death due to any cause, disease risk index, donor type, patient age and comorbidity index. bMultivariate analysis for day 0–83 infections used Poisson regression, with the number of days at risk for infections as offset. Covariates considered were donor type and presence or absence of significant GVHD (grade 2–4 acute GVHD or chronic GVHD needing systemic therapy) in the day 0–83 interval.
Bone Marrow Transplantation (2014) 589 – 591
& 2014 Macmillan Publishers Limited
Letter to the Editor
591 role. For example, the earlier start of cyclosporine by Long-Boyle might have led to a decreased glomerular filtration rate5 and thus higher F-ara-A levels on day 0, possibly explaining why anti-GVHD effect was detected in Long-Boyle’s but not our study.); (3) cord blood was the predominant graft type in Long-Boyle’s study; the cord blood stem cells may have been more sensitive to the myelotoxic effects of F-ara-A compared with the adult donor blood stem cells used in our study. In conclusion, day 0 F-ara-A levels are highly variable (1–104 ng/mL), probably due to variable, though normal, 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 no later than 48 h before graft infusion and to patients with normal renal function. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We would like to thank the patients for participating in research that could not benefit them but only future patients. This study could not have happened without the dedication of Mamta Kantharia, Ramya Krishnan, Glennis Doiron, as well as the staff of the Alberta Blood and Marrow Transplant Program, including data managers (including Diana Quinlan and Maggie Young), inpatient and outpatient nurses (led by Lorraine Harrison, Joanne Leavitt and Naree Ager), and physicians, including
Drs Douglas A. Stewart, Nancy Zacarias, Nizar Bahlis, Michelle Geddes, Mona Shafey, Loree Larratt, Minakshi Taparia and Robert Turner. This work was in part funded by Alberta Heritage Foundation for Medical Research, Canada Research Chair Program, Alberta Innovates-Health Solutions and Alberta Cancer Foundation.
CD Griffiths, ESM Ng, SB Kangarloo, TS Williamson, MA Chaudhry, R Booker, P Duggan, P Yue, L Savoie, C Brown, N Cox-Kennett, JA Russell, A Daly and J Storek Department of Internal Medicine, University of Calgary & Alberta Health Services, Calgary, Alberta, Canada E-mail: cameron.griffi[email protected] REFERENCES 1 Ricci F, Tedeschi A, Morra E, Montillo M. Fludarabine in the treatment of chronic lymphocytic leukemia: a review. Ther Clin Risk Manag 2009; 5: 187–207. 2 Bonin M, Pursche S, Bergeman T, Leopold T, Illmer T, Ehninger G et al. F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bone Marrow Transplant 2007; 39: 201–206. 3 Long-Boyle JR, Green KG, Brunstein CG, Cao Q, Rogosheske J, Weisdorf DJ et al. High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation. Bone Marrow Transplant 2011; 46: 20–26. 4 Hoegh-Petersen M, Amin MA, Liu Y, Ugarte-Torres A, Williamson TS, Podgorny PJ et al. Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse. Bone Marrow Transplant 2013; 48: 105–114. 5 Naesens M, Kuypers D, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009; 4: 481–508.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
& 2014 Macmillan Publishers Limited
Bone Marrow Transplantation (2014) 589 – 591
LETTER TO THE EDITOR
Fludarabine metabolite level on day zero does not affect outcomes of hematopoietic cell transplantation in patients with normal renal function graft-vs-leukemia reaction) or decrease the likelihood of GVHD. In addition, a high day 0 level may be a surrogate for a high area under the time–concentration curve (AUC), which could be associated with decreased likelihood of relapse or increased likelihood of death due to organ toxicity. The goal of this study was to assess the relationship between day 0 F-ara-A levels and clinical outcomes. Conditioning of all patients included fludarabine, 50 mg/m2 daily from day 6 to day 2. For additional patient characteristics and methods, see Supplementary Material online. As expected, there was an inverse correlation between the day 0 F-ara-A levels and creatinine clearance (estimated with Cockroft–Gault equation using the average of daily creatinine determinations from day 6 to day 0; r ¼ 0.42, Po0.01, Spearman correlation). We found no cases of transplant-related neurotoxicity attributable to conditioning. In univariate analyses, there was no difference in median F-ara-A levels between patients who did and those who did not
10
10
10
1
1
1
Any cGVHD
10
10
10
1
1
1 N
Ye s
N
Ye s
PTLD 100
10
10
10
1
1
1 Ye s
N
Ye s
N
Relapse
o
100
o
100
Death
o
CMV reactivation
N
N
o
100
o
100
o
100
“Extensive”cGVHD
Ye s
Ye s
N
N
Ye s
aGVHD (gr. 3-4)
aGVHD (gr. 2-4)
F-Ara-A (ng/mL)
N o
100
o
100
o
100
Ye s
Fludarabine, an immunosuppressive and cytotoxic purine analog, is a common constituent of conditioning for hematopoietic cell transplantation (HCT). Fludarabine (F-ara-AMP) is a prodrug that is dephosphorylated in plasma to 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A). On entry into a cell, F-ara-A is phosphorylated to F-ara-ATP, which interferes with DNA replication, transcription and translation, and induces apoptosis.1,2 Owing to variable renal clearance,3 F-ara-A levels on day 0 (immediately before graft infusion) may be variable. The clinical relevance of the F-ara-A persisting in plasma on day 0 is unknown. High day 0 levels may negatively impact the hematopoietic stem cells or lymphocytes infused with the graft, which could increase the likelihood of infections or relapse (by abrogating a
Ye s
Bone Marrow Transplantation (2014) 49, 589–591; doi:10.1038/ bmt.2013.234; published online 27 January 2014
Non-relapse death
Figure 1. No significant difference in day 0 F-ara-A levels between patients with and those without GVHD, CMV reactivation above our threshold for preemptive antiviral therapy (25 000 IU/mL plasma), post-transplant lymphoproliferative disorder (PTLD), relapse, non-relapse death or death due to any cause. For each clinical outcome, P was 40.05 (range, 0.22–0.78). Mann–Whitney–Wilcoxon test was used. ‘Extensive’ cGVHD means chronic GVHD needing systemic therapy.
Letter to the Editor
590 develop acute GVHD (aGVHD) grade 2–4, aGVHD grade 3–4, any chronic GVHD, ‘extensive’ chronic GVHD (needing systemic therapy), CMV reactivation, post-transplant lymphoproliferative disorder, relapse, death or non-relapse death (Figure 1 and Supplementary Table 2). There was also no significant association between the F-ara-A levels and the rates of infections of all categories, except for bacterial infections and definite infections (defined as described Hoegh-Petersen et al.4) (Supplementary Table 3). 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 and those whose level was below the median of 14 ng/mL (Table 1, Supplementary Figure 1 and Supplementary Table 4). Given the clustering of most F-ara-A levels near the median (Figure 1), to assess for differences between patients with extreme levels we analyzed whether there was a difference in the likelihood of developing each outcome between patients with levels in the fourth quartile (21–104 ng/mL) and those with levels in the first quartile (1–9 ng/mL). Again, in this analysis, there was no significant difference for any outcome (Table 1 and Supplementary Figure 1). However, there was a trend toward more bacterial infections in patients with high F-ara-A levels (Table 1). As patients with high F-ara-A level experienced later neutrophil engraftment (Supplementary Table 3), we hypothesized that this caused the trend toward more bacterial infections. Thus, we compared the median day of engraftment between patients who did not and those who did develop X1 bacterial infection(s) (between day 0 and 83). We found no difference (median day 14 vs 14, P ¼ 0.55, Mann–Whitney– Wilcoxon test). We also tested for the correlation between the
day of neutrophil engraftment and the rate of day 0–83 bacterial infections, and found no correlation (Spearman’s r ¼ 0.0136, P ¼ 0.8619). Thus, the reason for the trend toward more bacterial infections in patients with higher F-ara-A levels remains unexplained. The results suggest that, within the power of this study, there is no significant impact of day 0 F-ara-A level on clinical outcomes. This may be due to the fact that even the patients with the highest quartile had relatively low F-ara-A levels (21–104 ng/mL), compared with B1000 ng/mL at 1–4 h after infusion of 30 mg/m2 of fludarabine.2 This is the first published analysis of the effect of F-ara-A day 0 level on clinical outcomes after HCT. The closest published study is that of Long-Boyle et al.,3 which demonstrated a lower risk of grade 2–4 aGVHD and an increased risk of non-relapse and overall mortality in patients with high F-ara-A AUC. Possible reasons for the apparently discrepant results between Long-Boyle’s and our studies are: (1) total exposure over a 5-day period from day 6 to 2 (AUC) was measured in the Long-Boyle’s study as opposed to day 0 levels in our study (Correlation between the AUC and the day 0 level may be imperfect, for example, because the time between the last fludarabine dose and graft infusion is variable (at our institution 48–72 h after the last fludarabine dose.); (2) conditioning in Long-Boyle’s study consisted of CY þ fludarabine þ TBI±ATG compared with BU þ fludarabine þ ATG±TBI in our study (GVHD prophylaxis included mycophenolate mofetil from day 3 plus cyclosporine from day 3 in LongBoyle’s study vs MTX from day þ 1 plus cyclosporine from day 1 in our study. Thus, different drug–drug interactions may have a
Table 1. Multivariate analysis of association between high fludarabine levels and outcomes, using log-binomial regression (for one-time outcomes)a, or Poisson regression (for infections)b Outcome
Above vs below median RR (95% CI)
aGVHD (grade 2–4) aGVHD (grade 3–4) Any cGVHD ‘Extensive cGVHD’ CMV reactivation PTLD Relapse Non-relapse death Death due to any cause
0.90 1.06 1.51 1.37 1.02 1.30 0.72 1.45 1.02
(0.53–1.62) (0.42–2.66) (0.54–4.21) (0.81–2.32) (0.61–1.71) (0.39–3.33) (0.40–1.29) (0.56–3.76) (0.47–2.21)
IRR (95% CI) Any infection Definite infection Viral infection Bacterial infection Fungal infection Any severe infection Definite severe infection
1.15 1.21 1.06 1.36 0.76 0.94 0.92
(0.88–1.50) (0.92–1.61) (0.73–1.54) (0.89–2.10) (0.20–2.88) (0.64–1.37) (0.62–1.36)
Fourth vs first quartile P-value 0.73 0.90 0.43 0.24 0.95 0.67 0.27 0.44 0.95 P-value 0.30 0.18 0.77 0.15 0.69 0.73 0.68
RR (95% CI) 0.77 0.71 0.72 1.21 1.16 0.97 0.55 1.19 0.85
(0.36–1.65) (0.25–2.06) (0.40–1.30) (0.62–2.37) (0.61–2.19) (0.24–2.95) (0.20–1.50) (0.35–3.00) (0.31–2.34)
IRR (95% CI) 1.27 1.35 1.24 1.59 0.64 1.03 0.98
(0.89–1.79) (0.30–1.96) (0.76–2.03) (0.90–2.81) (0.11–3.87) (0.64–1.68) (0.60–1.61)
P-value 0.50 0.53 0.28 0.58 0.65 0.97 0.24 0.78 0.75 P-value 0.19 0.11 0.39 0.10 0.63 0.88 0.95
Abbreviations: CI ¼ confidence interval; IRR ¼ incidence rate ratio of day 0–83 infections among patients with high vs low F-ara-A level; NRD ¼ non-relapse death; PTLD ¼ post-transplant lymphoproliferative disorder; RR ¼ risk ratio of outcome among patients with high vs low F-ara-A level, that is, above vs below median in the ‘above vs below median’ analysis, and above 75th percentile vs under 25th percentile in the ‘fourth vs first quartile’ analysis. High fludarabine levels were defined as levels above median (in the above vs below median analysis) or above 75th percentile (in the fourth vs first quartile analysis). a Multivariate analysis to determine whether patients with high F-ara-A level had a higher likelihood of developing the outcome (RR 41) or lower likelihood of the outcome (RRo1). Covariates considered were (1) for acute and chronic GVHD, donor type (HLA-matched sibling vs other), gender combination (male/male vs other) and patient age (above vs below 45 years); (2) for CMV reactivation above our institutional threshold for preemptive antiviral therapy (25 000 IU/mL plasma), CMV IgG serostatus pretransplant ( þ / þ , þ / , / þ , / ) and presence or absence of significant GVHD; (3) for PTLD, donor type, patient age, EBV serostatus pretransplant and presence or absence of significant GVHD (grade 2–4 acute GVHD or chronic GVHD needing systemic therapy) before PTLD onset; (4) for relapse, disease risk index (low-intermediate vs high-very high), donor type, gender combination and patient age; and (5) for non-relapse death and for death due to any cause, disease risk index, donor type, patient age and comorbidity index. bMultivariate analysis for day 0–83 infections used Poisson regression, with the number of days at risk for infections as offset. Covariates considered were donor type and presence or absence of significant GVHD (grade 2–4 acute GVHD or chronic GVHD needing systemic therapy) in the day 0–83 interval.
Bone Marrow Transplantation (2014) 589 – 591
& 2014 Macmillan Publishers Limited
Letter to the Editor
591 role. For example, the earlier start of cyclosporine by Long-Boyle might have led to a decreased glomerular filtration rate5 and thus higher F-ara-A levels on day 0, possibly explaining why anti-GVHD effect was detected in Long-Boyle’s but not our study.); (3) cord blood was the predominant graft type in Long-Boyle’s study; the cord blood stem cells may have been more sensitive to the myelotoxic effects of F-ara-A compared with the adult donor blood stem cells used in our study. In conclusion, day 0 F-ara-A levels are highly variable (1–104 ng/mL), probably due to variable, though normal, 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 no later than 48 h before graft infusion and to patients with normal renal function. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We would like to thank the patients for participating in research that could not benefit them but only future patients. This study could not have happened without the dedication of Mamta Kantharia, Ramya Krishnan, Glennis Doiron, as well as the staff of the Alberta Blood and Marrow Transplant Program, including data managers (including Diana Quinlan and Maggie Young), inpatient and outpatient nurses (led by Lorraine Harrison, Joanne Leavitt and Naree Ager), and physicians, including
Drs Douglas A. Stewart, Nancy Zacarias, Nizar Bahlis, Michelle Geddes, Mona Shafey, Loree Larratt, Minakshi Taparia and Robert Turner. This work was in part funded by Alberta Heritage Foundation for Medical Research, Canada Research Chair Program, Alberta Innovates-Health Solutions and Alberta Cancer Foundation.
CD Griffiths, ESM Ng, SB Kangarloo, TS Williamson, MA Chaudhry, R Booker, P Duggan, P Yue, L Savoie, C Brown, N Cox-Kennett, JA Russell, A Daly and J Storek Department of Internal Medicine, University of Calgary & Alberta Health Services, Calgary, Alberta, Canada E-mail: cameron.griffi[email protected] REFERENCES 1 Ricci F, Tedeschi A, Morra E, Montillo M. Fludarabine in the treatment of chronic lymphocytic leukemia: a review. Ther Clin Risk Manag 2009; 5: 187–207. 2 Bonin M, Pursche S, Bergeman T, Leopold T, Illmer T, Ehninger G et al. F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bone Marrow Transplant 2007; 39: 201–206. 3 Long-Boyle JR, Green KG, Brunstein CG, Cao Q, Rogosheske J, Weisdorf DJ et al. High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation. Bone Marrow Transplant 2011; 46: 20–26. 4 Hoegh-Petersen M, Amin MA, Liu Y, Ugarte-Torres A, Williamson TS, Podgorny PJ et al. Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse. Bone Marrow Transplant 2013; 48: 105–114. 5 Naesens M, Kuypers D, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009; 4: 481–508.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
& 2014 Macmillan Publishers Limited
Bone Marrow Transplantation (2014) 589 – 591
