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Biology of Blood and Marrow... Nov 2016The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing... (Review)
Review
The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing busulfan-based conditioning. The Committee sought to grade the relevant published studies (June 1, 2008 through March 31, 2016) according to criteria set forth by the Steering Committee for Evidence Based Reviews from ASBMT. Unfortunately, the published literature was too heterogeneous and lacked adequately powered and sufficiently controlled studies for this to be feasible. Despite this observation, the continued interest in this topic led the Practice Guidelines Committee to develop a list of most frequently asked questions (FAQs) regarding personalized busulfan dosing. This "Considerations" document is a list of these FAQs and their responses, addressing topics of practical relevance to hematopoietic cell transplantation clinicians.
Topics: Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Myeloablative Agonists; Precision Medicine; Transplantation Conditioning
PubMed: 27481448
DOI: 10.1016/j.bbmt.2016.07.013 -
American Journal of Hematology Mar 2023We report a randomized prospective phase 3 study, designed to evaluate the efficacy and tolerability of idarubicin plus busulfan and cyclophosphamide (IDA-BuCy) versus... (Randomized Controlled Trial)
Randomized Controlled Trial
Idarubicin plus BuCy versus BuCy conditioning regimens for intermediate-risk acute myeloid leukemia in first complete remission undergoing auto-HSCT: An open-label, multicenter, randomized phase 3 trial.
We report a randomized prospective phase 3 study, designed to evaluate the efficacy and tolerability of idarubicin plus busulfan and cyclophosphamide (IDA-BuCy) versus BuCy in autologous hematopoietic stem-cell transplantation (auto-HSCT) for intermediate-risk acute myeloid leukemia (IR-AML) patients in first complete remission (CR1). One hundred and fifty-four patients were enrolled and randomized to receive IDA-BuCy (IDA 15 mg/m2/day on days -12 to -10, Bu 3.2 mg/kg/day on days -7 to -4, and Cy 60 mg/kg/day on days -3 to -2) or BuCy. The 2-year incidence of relapse was 15.6% and 19.5% in IDA-BuCy and BuCy groups (p = 0.482), respectively. There was no significant overall survival (OS) and disease-free survival (DFS) benefit for IR-AML patients receiving IDA-BuCy (2-year OS 81.8% in IDA-BuCy vs. 83.1% in BuCy, p = 0.798; 2-year DFS 76.6% in IDA-BuCy vs. 79.2% in BuCy, p = 0.693). Grade 3 or worse regimen-related toxicity (RRT) was reported for 22 (28.9%) of 76 and 9 (12.0%) of 75 patients in two groups (p = 0.015), respectively. AEs within 100 days with an outcome of death were reported for 4 (5.3%) and 0 patients in two groups. In conclusion, IDA-BuCy has higher RRT and similar anti-leukemic activity compared with BuCy in IR-AML patients in CR1 undergoing auto-HSCT. Thus, caution should be taken when choosing IDA-BuCy for IR-AML patients in CR1 with auto-HSCT. This trial is registered with ClinicalTrials.gov, NCT02671708, and is complete.
Topics: Humans; Idarubicin; Leukemia, Myeloid, Acute; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Busulfan; Transplantation Conditioning; Retrospective Studies
PubMed: 36588387
DOI: 10.1002/ajh.26800 -
Bone Marrow Transplantation Jul 2023Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT)....
Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at -52 or -69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at -52 (rs3957356) and -69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.
Topics: Adult; Humans; Busulfan; Pharmacogenetics; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Polymorphism, Genetic; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37085674
DOI: 10.1038/s41409-023-01963-z -
Biology of Blood and Marrow... Nov 2013Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious...
Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.
Topics: Antineoplastic Agents, Alkylating; Busulfan; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous
PubMed: 24029650
DOI: 10.1016/j.bbmt.2013.08.014 -
Journal of Ovarian Research Aug 2023Explore the therapeutic role of human umbilical mesenchymal stem cells (hUMSCs) transplantation for regeneration of ECM components and restoration of follicular...
OBJECTIVES
Explore the therapeutic role of human umbilical mesenchymal stem cells (hUMSCs) transplantation for regeneration of ECM components and restoration of follicular development in mice.
BACKGROUND
The extracellular matrix (ECM) is crucial to maintain ovary function and regulate follicular development, as it participates in important cell signaling and provides physical support to the cells. However, it is unknown how hUMSCs affect the expression of ECM-related genes in ovaries treated with cyclophosphamide (CTX) and busulfan (BUS).
METHODS
In the present study, we used 64 six- to eight-week-old ICR female mice to established mouse model. The mice were randomly divided into four groups (n = 16/group): control, POI, POI + hUMSCs, and POI + PBS group. The premature ovarian insufficiency (POI) mouse model was established by intraperitoneal injection of CTX and BUS for 7days, then, hUMSCs or PBS were respectively injected via the tail vein in POI + hUMSCs or POI + PBS group. Another 7days after injection, the mice were sacrificed to harvest the ovary tissue. The ovaries were immediately frozen with liquid nitrogen or fixed with 4% PFA for subsequent experiments. To screen differentially expressed genes (DEGs), we performed transcriptome sequencing of ovaries. Thereafter, a Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the related biological functions. Retrieval of interacting genes for ECM-related DEGs was performed using the function of STRINGdb (version 2.6.5) to evaluate potential protein-protein interaction (PPI) networks. Furthermore, qRT-PCR and IHC were performed to assess the differential expression of selected DEGs in control, damaged, hUMSCs-transplanted and non-transplanted ovaries.
RESULTS
Chemotherapy caused mouse ovarian follicular reserve depletion, and hUMSCs transplantation partially restored follicular development. Our results revealed that ECM-receptor interaction and ECM organization were both downregulated in the damaged ovaries. Further investigation showed that ECM-related genes were downregulated in the CTX and BUS treatment group and partially rescued in hUMSCs injection group but not in the PBS group. qRT-PCR and IHC verified the results: collagen IV and laminin gamma 3 were both expressed around follicle regions in normal ovaries, chemotherapy treatment disrupted their expression, and hUMSCs transplantation rescued their localization and expression to some extent.
CONCLUSION
Our data demonstrated that ECM-related genes participate in the regulation of ovarian reserve, hUMSCs treatment rescued abnormal expression and localization of collagen IV and laminin gamma 3 in the damaged ovaries. The results suggest that hUMSCs transplantation can maintain ECM-stable microenvironments, which is beneficial to follicular development.
Topics: Humans; Female; Animals; Mice; Mice, Inbred ICR; Laminin; Menopause, Premature; Primary Ovarian Insufficiency; Extracellular Matrix; Busulfan; Collagen
PubMed: 37620943
DOI: 10.1186/s13048-023-01217-y -
Discovery Medicine Mar 2015The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic... (Review)
Review
The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic myeloid leukemia (CML) patients who fail or are intolerant to TKIs. Its long-term cost effectiveness compared to TKIs, however, has maintained its use as front-line treatment in some areas. Advances in HCT, including the development of intravenous busulfan and plasma assays permitting dose adjustment, have improved results of HCT in CML. Improved supportive care has lowered the incidence of non-relapse mortality and improved survival. The availability of reduced-intensity preparative regimens, molecular typing of unrelated donors, and the use of cord blood and haploidentical donors has expanded the application of HCT to nearly any patient with an appropriate indication. From 2006 to 2010, approximately one thousand HCTs were performed annually in patients with CML. Better understanding of recent advances will improve the appropriate use and results of HCT in patients with CML.
Topics: Antineoplastic Agents; Busulfan; Combined Modality Therapy; Cost-Benefit Analysis; Fetal Blood; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Postoperative Period; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Treatment Outcome
PubMed: 25828525
DOI: No ID Found -
Biology of Blood and Marrow... Feb 2009Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and...
Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.
Topics: Adolescent; Area Under Curve; Busulfan; Child; Child, Preschool; Drug Interactions; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Infant; Melphalan; Mucositis; Retrospective Studies; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 19167683
DOI: 10.1016/j.bbmt.2008.11.022 -
Bone Marrow Transplantation Jan 2024Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This... (Randomized Controlled Trial)
Randomized Controlled Trial
Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.
Topics: Child; Humans; Busulfan; Prospective Studies; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Vidarabine; Graft vs Host Disease
PubMed: 37925531
DOI: 10.1038/s41409-023-02135-9 -
BMC Complementary Medicine and Therapies Jun 2022Busulfan is an antineoplastic medication that is broadly utilized for cancer treatment. It affects the testicular function and leads to sterility. The present study...
BACKGROUND
Busulfan is an antineoplastic medication that is broadly utilized for cancer treatment. It affects the testicular function and leads to sterility. The present study aimed to evaluate the effects of ellagic acid on testicular tissue changes, sexual hormones, antioxidant defense system, and caspase-9 and Bcl2 gene expression in the busulfan-induced relative sterile rat model.
METHODS
This is an interventional-experimental animal study that was performed on 65 Adult male rats; they were randomly divided into five groups including control (1 ml of 0.9% normal saline), ellagic acid (50 mg/kg); busulfan (10 mg/kg); and busulfan plus ellagic acid (10 mg/kg and 50 mg/kg). At the end of the experiment, blood samples were collected, and plasma levels of sex hormones, antioxidant system, apoptosis-related genes, and testis histology were assessed.
RESULTS
Busulfan reduced the levels of serum testosterone, total antioxidant capacity, gene expression of Bcl2, testicular volume, seminiferous tubule, germinal epithelium, interstitial tissue volume, and the number of spermatogonia, spermatocyte, round spermatid, elongated spermatid, Sertoli cells and Leydig cells (p < 0.05). Busulfan administration resulted in a significant increase (p < 0.05) in the level of LH, FSH, malondialdehyde, and caspase 9. Busulfan + ellagic acid (50 mg/kg) showed higher serum levels of testosterone, gene expression of Bcl-2 and antioxidant markers, and lower LH, FSH levels, and gene expression of caspase 9 compared to the Busulfan-treated rats (p < 0.05). Stereological parameters were also ameliorated in the group treated with Busulfan+ 50 mg/kg ellagic acid (p < 0.05).
CONCLUSION
In conclusion, the consumption of ellagic acid may have beneficial effects on the antioxidant defense system, sexual hormone abnormality, and testicular tissue damage induced by busulfan.
Topics: Animals; Antioxidants; Apoptosis; Busulfan; Caspase 9; Ellagic Acid; Follicle Stimulating Hormone; Infertility; Male; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; Spermatozoa; Testis; Testosterone
PubMed: 35739528
DOI: 10.1186/s12906-022-03650-w -
Journal of Clinical Pharmacology Oct 2011Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral busulfan to lower rates of... (Clinical Trial)
Clinical Trial
Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient's average clearance was used for analyses. The average (± standard deviation) busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV busulfan. Oral busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral busulfan clearance and similar rates of achieving the target busulfan exposure. Clearance of IV busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype.
Topics: Administration, Oral; Adolescent; Adult; Busulfan; Female; Gene Expression Regulation; Genotype; Glutathione Transferase; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Injections, Intravenous; Male; Middle Aged; Young Adult
PubMed: 21135089
DOI: 10.1177/0091270010382915