A modified busulfan and cyclophosphamide preparative regimen for allogeneic transplantation in myeloid malignancies

Cai, Xiaojin; Wei, Jia-Ling; He, Yi; Yang, Deqing; Jiang, Erlie; Huang, Yong; Han, Mingzhe; Feng, Sizhou

doi:10.1007/s11096-014-0036-5

Cited by 10 publications

(14 citation statements)

References 34 publications

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“…The high TRM in the alloHSCT group is largely attributable to early mortality. Despite advances in supportive care, and the procedure of alloHSCT improved, the high rate of early mortality is still an important limitation for alloHSCT[ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Intermediate-Risk Acute Myeloid Leukemia Adult Patients in First Complete Remission: A Meta-Analysis of Prospective Studies

Wang

Zhu

et al. 2015

PLoS ONE

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Hematopoietic stem cell transplantation (HSCT) and consolidation chemotherapy have been used to treat intermediate-risk acute myeloid leukemia (AML) patients in first complete remission (CR1). However, it is still unclear which treatments are most effective for these patients. The aim of our study was to analyze the relapse-free survival (RFS) and overall survival (OS) benefit of allogeneic HSCT (alloHSCT) for intermediate-risk AML patients in CR1. A meta-analysis of prospective trials comparing alloHSCT to non-alloHSCT (autologous HSCT [autoHSCT] and/or chemotherapy) was undertaken. We systematically searched PubMed, Embase, and the Cochrane Library though October 2014, using keywords and relative MeSH or Emtree terms, 'allogeneic'; 'acut*' and 'leukem*/aml/leukaem*/leucem*/leucaem*'; and 'nonlympho*' or 'myelo*'. A total of 7053 articles were accessed. The primary outcomes were RFS and OS, while the secondary outcomes were treatment-related mortality (TRM) and relapse rate (RR). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for each outcome. The primary outcomes were RFS and OS, while the secondary outcomes were TRM and RR. We included 9 prospective controlled studies including 1950 adult patients. Patients with intermediate-risk AML in CR1 who received either alloHSCT or non-alloHSCT were considered eligible. AlloHSCT was found to be associated with significantly better RFS, OS, and RR than non-alloHSCT (HR, 0.684 [95% CI: 0.48

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Section: Discussionmentioning

confidence: 99%

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Intermediate-Risk Acute Myeloid Leukemia Adult Patients in First Complete Remission: A Meta-Analysis of Prospective Studies

Wang

Zhu

et al. 2015

PLoS ONE

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“…Busulfan (Bu) is a bifunctional alkylating agent routinely used in preparative regimens prior to hematopoietic stem cell transplantation (HSCT) in treatment of various malignancies and inherited disorders . It is a cell cycle nonspecific agent which can ablate bone marrow, and is usually used in combination with other cytotoxic drugs, such as cyclophosphamide, fludarabine . In vivo studies have shown that the pharmacokinetics of busulfan is adequately described by one compartment open model with a half‐life of 2‐3 hours .…”

Section: Introductionmentioning

confidence: 99%

“…9 Over the past 15 years, several HSCT centers have personalized either oral or intravenous Bu using therapeutic drug monitoring (TDM), and TDM has been the standard of care for HSCT patients in these centers. 13 It has been recommended [14][15][16][17][18] that an area under the plasma concentration vs time curve from 0 to 6 hours (AUC [0][1][2][3][4][5][6] of busulfan should between 900 and 1500 μmol/L/min. AUC 0-6 lower than 900 μmol/L/min is associated with engraftment failure, 16,18 while AUC 0-6 higher than 1500 μmol/L/min results in hepatic veno-occlusive disease.…”

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confidence: 99%

Population pharmacokinetics analysis of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation

Xie

Yang

et al. 2017

Clin Exp Pharma Physio

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There are several reports describing population pharmacokinetic (popPK) models of busulfan (BU). However, limited information is available in Chinese hematopoietic stem cell transplantation (HSCT) patients. The present study aimed to establish a popPK model of intravenous BU in Chinese HSCT patients for individualized drug therapy. The popPK model of BU was developed from a total of 284 concentration-time points from 53 patients. The effects of demographic and biochemical covariates were investigated by nonlinear mixed effect model (NONMEM) software. Plots, visual predictive check (VPC), bootstrap and normalized prediction distribution error (NPDE) were performed to determine the stability and the reliability of the final model. A one-compartment model with first-order elimination process was confirmed as the final structural model for BU. For a typical patient whose body surface area (BSA) is 1.7 m , the population typical values of CL and Vd were 11.86 L/h, and 48.2 L, respectively. The result suggested BSA showed significant influence on CL and Vd (P<.001). Plots revealed the final model was performing a goodness fit. The steady rate verified by bootstrap was 100%, relative deviation was less than 4.00%, estimated value of final model was in the 95% confidence interval (CI). The VPC results showed the observed values were almost all positioned within the 5th and 95th CIs. The mean and variance of the NPDE were 0.0363 (Wilcoxon signed-rank test, 0.298) and 0.877 (Fisher variance test, 0.134; SW test of normality, 0.108), respectively. The global adjusted P value was 0.305, which indicated that the prediction of the BU popPK model was adequate. A physician-friendly Microsoft Excel-base tool was implemented using the final popPK model for designing individualized dosing regimens.

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“…Moreover, even if we had not identified this pathway in our in silico analysis of the RNAseq data, it was described that an increase in lipid peroxidation was observed in busulfan-treated testes after 1–2 weeks [ 22 ], suggesting an increase in reactive oxygen species (ROS) production. Indeed, mice treated with melatonin after busulfan injection showed enhanced spermatogenesis [ 23 ], and melatonin drives the expression of MnSOD (manganese superoxide dismutase), which counteracts apoptosis caused by high levels of busulfan-induced ROS [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

Analysis of the Reversible Impact of the Chemodrug Busulfan on Mouse Testes

Thirouard

Holota

Monrose

et al. 2021

Cells

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Spermatogenesis is a process within the testis that leads to the production of spermatozoa. It is based on a population of spermatogonial stem cells, which have the capacity to self-renew and to differentiate throughout life to ensure the functions of reproduction are maintained. Male fertility disorders are responsible for half of the cases of infertility in couples worldwide. It is well known that cancer treatments are associated with reversible or irreversible fertility disorders. Busulfan (Bu) is an alkylating agent that significantly inhibits spermatogenesis. The present study relied on a combination of in vivo and in vitro approaches as well as RNAseq analysis to characterize the effects of Bu, in which mouse testes were used as a model. An in silico analysis revealed that many of the Bu-modulated genes are potentially regulated by the SIN3 Transcription Regulator Family Member A (SIN3A) and E2F Transcription Factor (E2F) families of transcription factors. The results demonstrate that the deregulated genes function in processes related to the cell cycle, DNA repair, and cell death mechanisms, including the Tumor Protein 53 (TP53) pathway. This reinforces the role of the TP53 signaling pathway as a major player in Bu effects. In addition, Bu altered the patterns of mRNA accumulation for various genes in undifferentiated spermatogonia. This work provides significant insight into the kinetics and impacts of busulfan, which could pave the way for developing strategies to minimize the impact of chemodrugs and, thus, could lead to germ cell lineage regeneration following anticancer treatments.

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A modified busulfan and cyclophosphamide preparative regimen for allogeneic transplantation in myeloid malignancies

Abstract: The new regimen was associated with a low relapse rate, low incidence and severity of graft versus host disease and satisfactory survival for patients with myeloid malignancies.

Cited by 10 publications

References 34 publications

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Intermediate-Risk Acute Myeloid Leukemia Adult Patients in First Complete Remission: A Meta-Analysis of Prospective Studies

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Intermediate-Risk Acute Myeloid Leukemia Adult Patients in First Complete Remission: A Meta-Analysis of Prospective Studies

Population pharmacokinetics analysis of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation

Analysis of the Reversible Impact of the Chemodrug Busulfan on Mouse Testes

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