http://orcid.org/0000-0003-4229-7749
Figures
Abstract
Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.
Citation: Benadiba J, Ansari M, Krajinovic M, Vachon M-F, Duval M, Teira P, et al. (2018) Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children. PLoS ONE 13(4): e0193862. https://doi.org/10.1371/journal.pone.0193862
Editor: Zoran Ivanovic, EFS, FRANCE
Received: November 3, 2017; Accepted: February 20, 2018; Published: April 2, 2018
Copyright: © 2018 Benadiba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Unrelated umbilical cord blood transplant (UCBT) after a myeloablative conditioning regimen is a valid option for treatment of high-risk myeloid malignancies in children without a related donor, providing survival rates similar to unrelated HSCT donors[1–3].
Busulfan (Bu), a bi-functional alkylating agent, is used since 1980s in hematopoietic stem cell transplantation (HSCT) as part of the myeloablative conditioning regimen in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), both in children and adults[4]. Bu-based conditioning regimens have been proposed in children as an alternative to total body irradiation (TBI), in order to avoid growth delay and other long lasting side effects related to the use of TBI [5, 6]. Intravenous (IV) Bu has replaced oral Bu in many HSCT centers since it has a more predictable bioavailability. IV Bu has been associated with higher event free survival (EFS), lower transplant-related mortality (TRM) and toxicity compared to oral Bu[7, 8]. However, there are still important variations in Bu pharmacokinetics (PK) between patients that are associated with increased risk of graft failure and toxicity, such as hepatic veno-occlusive disease (VOD) or graft versus host disease (GvHD)[9–11]. Furthermore, intra- and interpatient Bu PK variability seems to be more important in children[12, 13]. It has been hypothesized that variability in Bu PK and treatment outcomes might be predicted by genetic variants of enzymes involved in the metabolism of Bu[14]. To optimize treatment with Bu, many transplant centers use therapeutic drug monitoring (TDM) and subsequent dose adjustment.
The objective of this study was to analyze results of myeloablative conditioning regimen based on IV Bu for AML and MDS, after unrelated UCB transplantation in children, and to evaluate the impact of Bu PK on the different outcomes after HSCT.
Patients and methods
This was a single-center study including 36 out of 49 children with a myeloid malignancy who underwent allogeneic HSCT with IV Bu as part of a myeloablative conditioning regimen at CHU Sainte-Justine in Montreal, Canada, between December 2000 and April 2012. From 2008, data were prospectively collected (Clinicaltrials.gov identifier: NCT01257854). Parents signed informed consent for collection and inclusion of their child’s HSCT data in our HSCT data registry. Approval from the Institutional Ethics Board was obtained to perform this study. Thirteen out of 49 patients who didn’t have signed informed consent were excluded from this study.
Myeloablative conditioning regimen consisted of 16 doses of IV Bu, every 6 hours, from day -9 to day -6 before HSCT, according to age (16mg/m2/dose in infants less than 3 months old, 0.8 mg/kg/dose if less than 1 year of age, 1 mg/kg/dose for children more than one year old and 0.8 mg/kg/dose for children more than 4 years old) followed by a PK-guided dose adjustment (based on this first dose) performed at the fifth dose level[7]. Bu was infused over 2 hours. Blood samples were collected for PK immediately before and at 15, 30, 60, 120, 180, and 240 minutes after the first dose. Plasma Bu concentrations were determined using a modified high-performance liquid chromatography assay[15] and was usually available before the fifth dose. Based on the first dose PK parameters, further doses of Bu were adjusted from the fifth dose onward to achieve a steady-state concentration (Css) between 600–900 ng/mL. This was achieved by estimating maximum and minimum plasma concentrations of Bu at the ninth dose based on first-dose clearance in a noncomportmental model for continuous IV infusion. A factor was calculated for adjustment of these concentrations to have a mean plasma concentration of 600–900 ng/mL at the ninth dose and then doses were adjusted with consideration of the adjustment factor. Bu PK was not done on subsequent Bu doses after first dose for most patients.
Bu was combined with Cyclophosphamide (Cy) with a cumulative dose of 200 mg/kg over 4 days, Melphalan 135 mg/m2 or Cy 120 mg/kg and Etoposide 30 mg/kg. Cyclosporin A and steroids were used as graft-versus host disease (GvHD) prophylaxis and 35 patients received antithymocyte globulins (ATG). Granulocyte colony-stimulating factor was used until neutrophils reached > 5x109/L for 2 days after UCBT for all patients. Prophylaxis for seizure was initiated 24 hours before Bu IV and continued for at least 24 hours after the end of Bu with lorazepam or midazolam for all but one patient, who received phenytoin. Fluconazole was administered as part of a supportive care regimen after the last dose of Bu and antiemetics were routinely administered throughout the conditioning regimen. Acyclovir was given as prophylaxis for herpes virus, and trimethoprim/sulfamethoxazole for pneumocystis jiroveci prophylaxis. Ursodeoxycholic acid was given to every patient as VOD prophylaxis.
Neutrophil recovery was defined as the first of 3 consecutive days of absolute neutrophil count ≥0.5 x 109/L. Platelet recovery was defined as the first of 7 consecutive days of platelet counts ≥50 x 109/L without transfusion. Primary graft failure or rejection was defined by persistent pancytopenia with no evidence of hematologic recovery of donor cells beyond 42 days after transplantation and secondary graft failure by a rapid decrease in neutrophil count and chimerism after successful engraftment. Acute GvHD (aGvHD) grading was based on the 1994 Consensus Conference on Acute GvHD Grading[16]. VOD was diagnosed according to Seattle criteria[17]. Non-relapse mortality (NRM) was defined as all causes of deaths after transplant not related to relapse. Time to relapse was calculated from the time between transplant and relapse. Event-free survival (EFS) was defined as the time from transplant until death, relapse, or graft failure, whichever occurred first. Overall survival (OS) was the time between transplantation and last contact or death of any cause.
For study variables, median value/range was reported for continuous variable and frequency/percentage for categorical variable. For statistical analysis, each continuous variable was dichotomized in 2 groups based on median value. A median Css of 576.5ng/mL was observed after the first Bu dose in the cohort, which did not differ by more than 5% from the lower limit of the targeted Css range. Hence, 600 ng/mL was chosen as the cut-off to dichotomize patients groups. Cumulative incidence of neutrophil and platelet recovery, grade 2–4 aGvHD, NRM, relapse, hemorrhagic cystitis (HC), VOD, and lung toxicity were calculated using the cumulative incidence (CI) estimator, with death as a competitive event (relapse for NRM). Probabilities of OS and EFS were calculated using the Kaplan–Meier method and log-rank test in univariate analysis. Multivariate analysis for OS and EFS was performed using Cox proportional hazards regression. Variables included in the multivariate analysis included Css, median infused nucleated cells per Kg and HLA compatibility (both known to influence UCBT outcomes after UCBT). Variables with a p<0.05 in univariate analysis were also included in the model. Two-sided p values were represented and p<0.05 was considered as statistically significant. Statistical analyses were performed using IBM SPSS Statistics 20 (IBM Corp, Armonk, NY) and Easy R software[18]. Approval from the Institutional Ethics Board (“Comité d’éthique de la recherche du CHU Sainte-Justine”) was obtained to perform this study.
Results
Median follow-up was 29.8 (0.9–113.4) months. Median age at transplant was 5.9 (0.6–19.3) years. Of 36 patients, 21 (58.3%) were male. Median weight was 25 (6.9–85.7) kg. There were 23 AML and 13 MDS. Cytogenetics were normal for 10 patients, five had monosomy7, four deletion 5q, four trisomy 21 and three MLL rearrangements. For four patients, cytogenetics were associated with a good prognosis, including one case with t(8;21), two with inversion 16, and one patient with t(15;17). Ten and 13 patients with AML were transplanted in first remission (CR1) or second remission (CR2)/ advanced phase of disease (>CR2 or in relapse), respectively. Thirty-three patients received a single UCBT. Eight, 13 and 15 patients received a 6/6, 5/6 and 3-4/6 HLA-matched graft. Median infused nucleated cells (NC) and CD34+ cells were 5.5 (0.51–29.09) x 107/kg and 2.2 (0.77–25.5) x 105/kg of recipient body weight, respectively. Bu was combined with Cy for 33 patients, Melphalan for 2 patients and Cy/Etoposide for one patient.
Table 1 summarizes the patients and transplant characteristics.
Median Css at the first dose was 576.5 (399–1153) ng/mL. Twenty-two patients had a first-dose Css below 600 ng/mL, and 14 above. For 9 patients, the initial prescribed dose of Bu was not changed (n = 5) or changed by less than 10% (n = 4). For 3 patients, initial prescribed dose of Bu was decreased, and for 24 patients the initial prescribed dose of Bu was increased (median increase 25%—range: 14%–56.2%). Median Bu clearance was 4.17 (2.06–5.87)mL/min/kg.
Cumulative incidence (CI) of neutrophil recovery at the 60th day post-transplant was 87.5% and platelet recovery at day +150 was 85.7%. Median time to neutrophil and platelet recovery was 22 days and 73 days, respectively. There were one primary and one secondary graft failure. CI of neutrophil recovery according to Css was 100% for Css <600 ng/mL, and 67.9% for Css > 600 ng/mL (p = 0.01) and CI of platelet recovery was 95.5% for Css < 600 ng/mL, and 70.5% for Css > 600 ng/mL (p = 0.04). No other variable was associated with neutrophil or platelet recoveries. Cumulative incidence of grade 2–4 aGvHD at day +180 was 15.1% and was not associated with any variable, or influenced by Bu PK. CI of hemorrhagic cystitis was 30.6%, and was significantly higher for patients with a Css > 600 ng/mL (50%) comparing to patients with Css < 600 ng/ml (18%—p = 0.04). Incidence of VOD was 6%, and occurred only in patients with Css > 600 ng/mL. Two cases of severe lung toxicity (acute respiratory distress syndrome) were observed, one patient on each group of Css. Cumulative incidence of relapse was 33.4% at 5 years and there was a trend of less relapse for patients with MDS (p = 0.08) and for those receiving a 6/6 compatible cord blood (p = 0.07). Cumulative incidence of NRM at 5 years was 11.1%. The only factor influencing NRM in univariate analysis, was Bu Css; the NRM was 0% vs. 28.6% for Css < and > 600 ng/mL, respectively (p = 0.009) (Fig 1).
Event-free survival (EFS) and overall survival (OS) were 50% and 63% respectively, for the whole population. Bu Css was shown to be the only predicting variable in univariate analysis: EFS: 64% vs. 29% for Css < and > 600 ng/mL, respectively (p = 0.006—Fig 2) and OS: 81% vs. 37.5% for Css < and > 600 ng/mL, respectively (p = 0.006- Fig 3).
In multivariate analysis, Css was the only variable to influence OS (HR: 5.2 [95% CI: 1.26–21.5] p = 0.02) and EFS (HR: 3.83 [95% CI: 1.33–11.05] p = 0.01).
Discussion
Conditioning regimens including total body irradiation (TBI) in combination with high dose chemotherapy have been used in patients with AML since the 1970s, and such regimens are known to be effective in achieving engraftment and eradicating disease[6]. Bu-based myeloablative regimens given before HSCT, are used in children as a TBI alternative to avoid late side effects such as growth impairments, cataracts, endocrinopathies, cognitive delay, and increased incidence of secondary malignancies associated with exposure to irradiation[6, 19]. There is no evidence of an advantage of using TBI on children with AML beyond CR1, since no significant difference in outcomes (EFS, OS, relapse) comparing TBI with Busulfan based conditioning regimen has been reported[6].
Oral Bu has a large inter-individual variability, with higher plasma concentrations associated with toxicity, whereas lower concentrations result in an increased risk of graft failure or relapse[8, 12, 20–24]. This might be particularly important in UCBT that carries a higher risk of graft failure. Intravenous formulation of Bu has gained popularity as pharmacokinetics is more predictable[19]. Nevertheless, inter- and intra-individual variability still exists, mostly in children. IV Bu dose with adjustment based on first-dose pharmacokinetics reduces the variability of Bu exposure among patients[25–27], improving engraftment, EFS and survival rates[20, 25].
Bu is primarily metabolized by liver glutathione S-transferase (GST) enzymes, predominantly by its variant GSTA1. This process depletes hepatocyte glutathione stores. Bu metabolism is influenced by GST enzyme activity, age, disease condition and co-medication[13]. Body surface area and body weight also contribute to PK variability[28]. Children appear to have a higher Bu clearance, resulting in a lower systemic exposure. The higher GST activity in children might explain the difference[12, 29]. GST polymorphisms influencing GST activity could partly contribute to the unexplained Bu variability[25, 30, 31]. A study of the European Blood and Marrow Transplant Group, confirmed that GST gene variants (GSTA1 and GSTM1) influence Bu PK and outcomes of HSCT in children[13].
In this study, we showed that Bu Css of the first dose seems to influence different outcomes after UCBT. A Bu Css below 600ng/mL associates with a better EFS, OS, NRM, and hematopoietic (neutrophil and platelet) recovery. On the other hand, there is no association between a lower first-dose Css and graft failure. However, since patients in this series had received a graft with a total dose of cells according to recommendation for a UCBT, this might have prevented a graft failure in most of patients. Unfortunately, there are missing data concerning the PK results on subsequent Bu doses in our study to confirm that the first dose Css, rather than the cumulative received Bu dose, explains the difference on the different outcomes. In a previous study including children who underwent HSCT with UCBT and UBMT for malignancies and non-neoplastic diseases, it was showed that Bu concentrations of the majority of children were in the targeted therapeutic range in subsequent doses[7]. The prognostic effect of the measured Bu Css was not due to an effect on relapse, since it was not affected by Css, similarly to what has been already described before[22, 32]. Rather, Bu Css at first dose seems to influence toxicity, as NRM occurred only in patients with a first-dose Css > 600 ng/mL. In adults, an association between higher Bu exposure and toxicity had been showed[11, 33]. But in pediatric patients, most authors reported absence of this association[34, 35]. Since all but two patients received Cy after IV Bu, glutathione (GSH) depletion in tissues, due to oxidative stress, might also have aggravated the tissue damage by Cy, initiating toxic events such as VOD, mucositis, hemorrhagic cystitis, lung toxicity, and others. Thus, the NRM seen with Css > 600 ng/mL could in fact be related to Cy toxicity after a GSH depletion by Bu, associate or not with a direct effect of Bu itself. It is known that Cy toxicity is highly dependent on GSH levels[36]. As some GST polymorphisms are associated with a lower Bu clearance, we can speculate that a higher Css is a surrogate marker for these polymorphisms[13]. Replacing Cy by other chemotherapy, such as fludarabine or tailored the first dose with an algorithm including demographics data as well as pharmacogenomics might improve the results of UCBT after Bu conditioning.
We showed that cumulative incidence of neutrophil and platelet recovery was higher when Bu Css was < 600 ng/mL. In contrast, in a study on 45 adults with chronic myeloid leukemia, there was no influence of Bu plasma levels on engraftment[21]. Similarly, Perkins et al reported that there was no correlation between first dose Bu AUC and bone marrow or lymphocyte chimerism studies around day 30 or day 100 after transplant with Bu and Fludarabine as conditioning before HSCT in adults[37]. The higher graft failure rate for those with first dose Bu Css >600 ng/mL can be explained by the higher NRM in the peri-engraftment period for these patients.
Differences in population and conditioning regimen might explain the differences between studies. Notwithstanding, our results are consistent with some studies conducted in children concerning the PK monitoring and individualization of Bu dosage regimen, where no graft rejection or graft failure were observed in pediatric bone marrow transplant recipients who received a lower total dose of Bu than those usually recommended[5]. Pediatric PK studies are however not uniform and large enough to define the relationship between Bu exposure and target therapeutic levels in children associated with optimal outcomes. Our study, including mainly Caucasian patients who received HSCT with only unrelated umbilical cord blood, with a uniformly PK targeted IV Bu and mostly together with Cy as myeloablative conditioning regimen, is unique to better define association between Bu exposure and outcomes of allogeneic UCBT. These are results from a single center, with uniform supportive care.
In conclusion, UCBT remains a useful treatment to patients with high-risk myeloid malignancies without a matching sibling donor, providing survival rates comparable to other graft sources. For patients receiving Bu and Cy as conditioning regimen before UCBT, initial first dose Bu PK (before adjustment to the cumulative dose) seems to be a significant prognostic factor in children, influencing neutrophil and platelet recovery, NRM, EFS and OS. A direct toxic effect of Bu and/or a synergistic toxic effect with Cy might explain the worst outcome when first dose IV Bu has a Css higher than 600ng/mL. It will be important to validate these results in a multicenter larger study and also to compare these results with patients who received a fixed dose of Bu. Finally, our data reinforces the importance of Bu therapeutic drug monitoring-guided dosing in pediatric HSCT patients.
References
- 1. Madureira AB, Eapen M, Locatelli F, Teira P, Zhang MJ, Davies SM, et al. Analysis of risk factors influencing outcome in children with myelodysplastic syndrome after unrelated cord blood transplantation. Leukemia. 2011;25(3):449–54. Epub 2010/12/08. pmid:21135856
- 2. Michel G, Rocha V, Chevret S, Arcese W, Chan KW, Filipovich A, et al. Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis. Blood. 2003;102(13):4290–7. Epub 2003/08/16. pmid:12920027
- 3. Michel G, Cunha R, Ruggeri A, O'Brien TA, Bittencourt H, Dalle JH, et al. Unrelated cord blood transplantation for childhood acute myelogenous leukemia: The influence of cytogenetic risk group stratification. Leukemia. 2016;30(5):1180–3. Epub 2015/09/16. pmid:26369981
- 4. Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. The New England journal of medicine. 1983;309(22):1347–53. Epub 1983/12/01. pmid:6355849
- 5. Bleyzac N, Souillet G, Magron P, Janoly A, Martin P, Bertrand Y, et al. Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. Bone marrow transplantation. 2001;28(8):743–51. Epub 2002/01/10. pmid:11781625
- 6. Sisler IY, Koehler E, Koyama T, Domm JA, Ryan R, Levine JE, et al. Impact of conditioning regimen in allogeneic hematopoetic stem cell transplantation for children with acute myelogenous leukemia beyond first complete remission: a pediatric blood and marrow transplant consortium (PBMTC) study. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2009;15(12):1620–7. Epub 2009/11/10.
- 7. Ansari M, Theoret Y, Rezgui MA, Peters C, Mezziani S, Desjean C, et al. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. Therapeutic drug monitoring. 2014;36(1):93–9. Epub 2013/09/26. pmid:24061446
- 8. Bartelink IH, Bredius RG, Ververs TT, Raphael MF, van Kesteren C, Bierings M, et al. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2008;14(1):88–98. Epub 2007/12/27.
- 9. Hassan M, Ljungman P, Bolme P, Ringden O, Syruckova Z, Bekassy A, et al. Busulfan bioavailability. Blood. 1994;84(7):2144–50. Epub 1994/10/01. pmid:7919328
- 10. Pidala J, Kim J, Anasetti C, Kharfan-Dabaja MA, Nishihori T, Field T, et al. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia. Journal of hematology & oncology. 2010;3:36. Epub 2010/10/12.
- 11. Dix SP, Wingard JR, Mullins RE, Jerkunica I, Davidson TG, Gilmore CE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone marrow transplantation. 1996;17(2):225–30. Epub 1996/02/01. pmid:8640171
- 12. Tse WT, Duerst R, Schneiderman J, Chaudhury S, Jacobsohn D, Kletzel M. Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant. Bone marrow transplantation. 2009;44(3):145–56. Epub 2009/02/03. pmid:19182832
- 13. Ansari M, Rezgui MA, Theoret Y, Uppugunduri CR, Mezziani S, Vachon MF, et al. Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients. Bone marrow transplantation. 2013;48(7):939–46. Epub 2013/01/08. pmid:23292236
- 14. Huezo-Diaz P, Uppugunduri CR, Tyagi AK, Krajinovic M, Ansari M. Pharmacogenetic aspects of drug metabolizing enzymes in busulfan based conditioning prior to allogenic hematopoietic stem cell transplantation in children. Current drug metabolism. 2014;15(3):251–64. Epub 2014/02/15. pmid:24524663
- 15. Rifai N, Sakamoto M, Lafi M, Guinan E. Measurement of plasma busulfan concentration by high-performance liquid chromatography with ultraviolet detection. Therapeutic drug monitoring. 1997;19(2):169–74. Epub 1997/04/01. pmid:9108645
- 16. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone marrow transplantation. 1995;15(6):825–8. Epub 1995/06/01. pmid:7581076
- 17. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Annals of internal medicine. 1993;118(4):255–67. Epub 1993/02/15. pmid:8420443
- 18. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone marrow transplantation. 2013;48(3):452–8. Epub 2012/12/05. pmid:23208313
- 19. Ansari M, Uppugunduri CR, Deglon J, Theoret Y, Versace F, Gumy-Pause F, et al. A simplified method for busulfan monitoring using dried blood spot in combination with liquid chromatography/tandem mass spectrometry. Rapid communications in mass spectrometry: RCM. 2012;26(12):1437–46. Epub 2012/05/18. pmid:22592987
- 20. Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, et al. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2009;15(2):231–41. Epub 2009/01/27.
- 21. Slattery JT, Clift RA, Buckner CD, Radich J, Storer B, Bensinger WI, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood. 1997;89(8):3055–60. Epub 1997/04/15. pmid:9108427
- 22. Copelan EA, Bechtel TP, Avalos BR, Elder PJ, Ezzone SA, Scholl MD, et al. Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation. Bone marrow transplantation. 2001;27(11):1121–4. Epub 2001/09/12. pmid:11551021
- 23. Dalle JH, Wall D, Theoret Y, Duval M, Shaw L, Larocque D, et al. Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results. Bone marrow transplantation. 2003;32(7):647–51. Epub 2003/09/18. pmid:13130310
- 24. Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP, et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone marrow transplantation. 1995;16(1):31–42. Epub 1995/07/01. pmid:7581127
- 25. Ansari M, Lauzon-Joset JF, Vachon MF, Duval M, Theoret Y, Champagne MA, et al. Influence of GST gene polymorphisms on busulfan pharmacokinetics in children. Bone marrow transplantation. 2010;45(2):261–7. Epub 2009/07/09. pmid:19584821
- 26. Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone marrow transplantation. 2004;33(10):979–87. Epub 2004/04/06. pmid:15064687
- 27. Dupuis LL, Sibbald C, Schechter T, Ansari M, Gassas A, Theoret Y, et al. IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2008;14(5):576–82. Epub 2008/04/16.
- 28. Paci A, Vassal G, Moshous D, Dalle JH, Bleyzac N, Neven B, et al. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Therapeutic drug monitoring. 2012;34(2):198–208. Epub 2012/03/13. pmid:22406655
- 29. Gibbs JP, Murray G, Risler L, Chien JY, Dev R, Slattery JT. Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan. Cancer research. 1997;57(24):5509–16. Epub 1998/01/04. pmid:9407960
- 30. Johnson L, Orchard PJ, Baker KS, Brundage R, Cao Q, Wang X, et al. Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation. Journal of clinical pharmacology. 2008;48(9):1052–62. Epub 2008/07/19. pmid:18635758
- 31. Kim I, Keam B, Lee KH, Kim JH, Oh SY, Ra EK, et al. Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation. Clinical transplantation. 2007;21(2):207–13. Epub 2007/04/12. pmid:17425746
- 32. Baker KS, Bostrom B, DeFor T, Ramsay NK, Woods WG, Blazar BR. Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia. Bone marrow transplantation. 2000;26(6):607–14. Epub 2000/10/21. pmid:11041565
- 33. Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2002;8(9):477–85. Epub 2002/10/11.
- 34. McCune JS, Gooley T, Gibbs JP, Sanders JE, Petersdorf EW, Appelbaum FR, et al. Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone marrow transplantation. 2002;30(3):167–73. Epub 2002/08/22. pmid:12189535
- 35. Zwaveling J, Bredius RG, Cremers SC, Ball LM, Lankester AC, Teepe-Twiss IM, et al. Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity. Bone marrow transplantation. 2005;35(1):17–23. Epub 2004/10/27. pmid:15502853
- 36. McCune JS, Batchelder A, Deeg HJ, Gooley T, Cole S, Phillips B, et al. Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2007;13(7):853–62. Epub 2007/06/21.
- 37. Perkins J, Field T, Kim J, Kharfan-Dabaja MA, Ayala E, Perez L, et al. Pharmacokinetic targeting of i.v. BU with fludarabine as conditioning before hematopoietic cell transplant: the effect of first-dose area under the concentration time curve on transplant-related outcomes. Bone marrow transplantation. 2011;46(11):1418–25. Epub 2010/12/07. pmid:21132026