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Transplantation and Cellular Therapy Aug 2022Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact...
Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients.
Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact of different myeloablative conditioning regimens, remain incompletely described. Here we compared the acute and long-term incidence of pulmonary toxicity (PT) after total body irradiation (TBI)- and busulfan-based myeloablative conditioning. We conducted this retrospective cohort study of 311 consecutive pediatric patients with leukemia or MDS who underwent allo-HSCT at Dana-Farber Cancer Institute/Boston Children's Hospital between 2008 and 2018. PT was graded using Common Terminology Criteria for Adverse Events version 5.0. The primary objective was to compare the cumulative incidence of grade ≥3 and grade 5 PT after TBI-based and busulfan-based myeloablative conditioning using Gray's test. Secondary objectives were to determine factors associated with PT and overall survival (OS) using competing risk analysis and Cox regression analyses, respectively. There was no significant difference between the TBI-conditioned group (n = 227) and the busulfan-conditioned group (n = 84) in the incidence of grade ≥3 PT (29.2% versus 34.7% at 2 years; P = .26) or grade 5 pulmonary toxicity (6.2% versus 6.1% at 2 years; P = .47). Age (hazard ratio [HR], 1.70, 95% confidence interval [CI], 1.11 to 2.59; P = .01), grade ≥2 PT prior to allo-HSCT or preexisting pulmonary conditions (HR, 1.84, 95% CI, 1.24 to 2.72; P < .01), acute graft-versus-host disease (GVHD) (HR, 2.50; 95% CI, 1.51 to 4.14; P < .01), and chronic GVHD (HR, 2.61; 95% CI, 1.26 to 5.42; P = .01) were associated with grade ≥3 PT on multivariable analysis. Grade ≥3 PT was associated with worse OS (81.1% versus 61.5% at 2 years; P < .01). In pediatric allo-HSCT recipients, rates of PT were similar in recipients of TBI-based and recipients of busulfan-based myeloablative conditioning regimens. Age, the presence of PT or preexisting pulmonary conditions prior to transplantation, and the development of either acute or chronic GVHD were associated with grade ≥3 PT post-transplantation. Furthermore, the occurrence of grade 3-4 PT post-transplantation was associated with inferior OS.
Topics: Busulfan; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Myelodysplastic Syndromes; Retrospective Studies; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation
PubMed: 35623615
DOI: 10.1016/j.jtct.2022.05.028 -
Expert Opinion on Drug Metabolism &... Sep 2017Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use,... (Review)
Review
Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized. Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted. Expert opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.
Topics: Adult; Animals; Antineoplastic Agents, Alkylating; Busulfan; Child; Drug Interactions; Drug Monitoring; Humans; Pharmacogenetics; Stem Cell Transplantation
PubMed: 28766962
DOI: 10.1080/17425255.2017.1360277 -
Biology of Blood and Marrow... Dec 2019It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell...
It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA), who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy-only conditioning, we replaced the single dose of total-body irradiation with BU at initial doses of 0.8 to 1.0 mg/kg and 0.6 to 0.8 mg/kg given i.v. every 12 hours for 4 doses. Patients received the first dose of i.v. busulfan on day -8, and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hours, 2 hours and 15 minutes, and 4, 5, 6, and 8 hours from the start of infusion. The remaining 3 doses of BU were given on days -7 and -6. Thirty-seven patients with available BU PK data with a median age of 9.2 years (range, 4.3 to 44 years) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort, a strong correlation between BU clearance and weight supports current practice of per kilogram dosing. However, not surprisingly, we show that the disease (ie, host) sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high-risk population. On the basis of our results, we propose an optimal BU concentration at steady-state level of ≤350 ng/mL (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. To our knowledge, this is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing an optimal BU target cutoff to achieve stable donor engraftment while avoiding excessive toxicity.
Topics: Adolescent; Adult; Allografts; Busulfan; Child; Child, Preschool; Fanconi Anemia; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation Conditioning
PubMed: 31326610
DOI: 10.1016/j.bbmt.2019.07.014 -
Transplantation and Cellular Therapy Nov 2021Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in...
Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Topics: Aged; Busulfan; Graft vs Host Disease; Humans; Melphalan; Middle Aged; Myelodysplastic Syndromes; Survival Analysis; Transplantation Conditioning; Vidarabine
PubMed: 34403791
DOI: 10.1016/j.jtct.2021.08.007 -
Molecular Medicine Reports Apr 2019Phosphoglycerate mutase 1 (PGAM1) is reported to be involved in spermatogenic dysfunction. However, the association between PGAM1 and busulfan‑induced...
Phosphoglycerate mutase 1 (PGAM1) is reported to be involved in spermatogenic dysfunction. However, the association between PGAM1 and busulfan‑induced hypospermatogenesis and spermatogenic cell apoptosis remains unclear. The aim of the current study was to investigate the association between PGAM1 expression and busulfan‑induced hypospermatogenesis, and the effect of PGAM1 expression on spermatogenic cell apoptosis. PGAM1 expression was detected in mouse models of busulfan‑induced hypospermatogenesis by western blotting, reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. Then, spermatogenic cell apoptosis in mouse models of busulfan‑induced hypospermatogenesis was assessed by TUNEL assay. The effect and potential mechanism of PGAM1 downregulation on spermatogenic cells were further investigated. The results indicated that PGAM1 expression was significantly downregulated in the mouse models of busulfan‑induced hypospermatogenesis, compared with those with normal spermatogenesis (P<0.05). Furthermore, the TUNEL assay revealed that the apoptosis of spermatogenic cells was accelerated in the mouse model of busulfan‑induced hypospermatogenesis. In addition, PGAM1 knockdown promoted the apoptosis of spermatogenic cells in vitro, which was associated with the P53/Caspase 3/Caspase 6/Caspase 9 signaling pathway. In conclusion, these data indicate that PGAM1 knockdown is associated with busulfan‑induced hypospermatogenesis and contributes to spermatogenic cell apoptosis by regulating the P53/Caspase 3/Caspase 6/Caspase 9 signaling pathway.
Topics: Animals; Apoptosis; Biomarkers; Busulfan; Gene Expression Regulation; Gene Knockdown Techniques; Male; Mice; Oligospermia; Phosphoprotein Phosphatases; Spermatozoa
PubMed: 30720109
DOI: 10.3892/mmr.2019.9930 -
Proceedings of the Royal Society of... May 1968
Topics: Busulfan; Female; Humans; Middle Aged; Primary Myelofibrosis
PubMed: 5655243
DOI: No ID Found -
BMC Pharmacology & Toxicology Jul 2022Administration of antineoplastic drugs may cause azoospermia driving to subfertility. Production of animal azoospermia models is essential for evaluating new treatment...
BACKGROUND
Administration of antineoplastic drugs may cause azoospermia driving to subfertility. Production of animal azoospermia models is essential for evaluating new treatment methods before therapeutic interventions in human setup. This study aimed to investigate the toxic effects of Busulfan (an anticancer drug) on some vital organs and describe the best method and appropriate dose of Busulfan to induce an animal azoospermia model.
METHODS
Rats were randomly assigned into four groups, treatment groups received 10 mg/kg, 40 mg/kg Busulfan intraperitoneally (IP), 5 mg/kg Busulfan intratesticular (IT), and control group. Blood, bone marrow, liver, renal, and testes samples were collected for histological (H&E staining), biochemical (serum levels of ALT, AST, ALP, creatinine, and urea), and hematological analyses.
RESULTS
Results revealed severe anemia and leukopenia in rats that received Busulfan via IP. By contrast, injection of 5 mg/kg Busulfan via IT did not cause anemia except with a mild decrease in RBC count. Non-significant differences in the M/E ratio were observed in all groups. The administration of 40 mg/kg of Busulfan led to evacuation and destruction in the spermatogenesis process with thin-walled seminiferous epithelium in most tubules, but in rats treated with 10 mg/kg of Busulfan, the normal spermatogenesis process was notified. IT injection of Busulfan contributed to the complete degradation of spermatogenesis in which all spermatogenic cells degenerated. In the renal tissue, hyperemia, extensive tubular necrosis degeneration, and hyaline casts were found after IP injection of Busulfan. In hepatic tissue, focal hemorrhagic, chronic cholangitis, and hepatocyte degeneration, and swelling were noticed. Biochemical analysis revealed apparent Busulfan toxicity of both hepatic and renal tissues in IP Busulfan-treated rats.
CONCLUSIONS
In summary, we found that the intratesticular injection of low doses of Busulfan (5 mg/kg) is a relatively non-invasive and safe method for producing the rat azoospermia model causing the least toxicity on vital organs.
Topics: Animals; Azoospermia; Busulfan; Disease Models, Animal; Humans; Injections; Injections, Intraperitoneal; Male; Rats; Spermatogenesis; Testis
PubMed: 35831882
DOI: 10.1186/s40360-022-00587-1 -
Therapeutic Drug Monitoring Dec 2023The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow...
BACKGROUND
The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively.
METHODS
A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate.
RESULTS
Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values.
CONCLUSIONS
The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.
Topics: Humans; Busulfan; Hematopoietic Stem Cell Transplantation; Laboratory Proficiency Testing; Laboratories; Drug Monitoring; Transplantation Conditioning
PubMed: 37199431
DOI: 10.1097/FTD.0000000000001107 -
Biology of Blood and Marrow... Sep 2020Allogeneic hematopoietic cell transplantation (HCT) for children with nonmalignant disorders is challenged by potential drug-related toxicities and poor engraftment....
Allogeneic hematopoietic cell transplantation (HCT) for children with nonmalignant disorders is challenged by potential drug-related toxicities and poor engraftment. This retrospective analysis expands on our single pediatric medical center experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity regimen to achieve sustained donor engraftment. Sixty-two patients received this regimen for their first HCT for a nonmalignant disorder between 2004 and 2018. Donors were matched sibling in 27%, 8/8 HLA allele-matched unrelated in 50%, and 7/8 HLA allele-mismatched in 23% (some of whom received additional immunoablation with thiotepa or clofarabine). Five patients experienced graft failure for a cumulative incidence of 8.4% (95% CI, 1 to 16%). In engrafted patients, the median donor chimerism in whole blood and CD3, CD14/15, and CD19 subsets at 1-year were 96%, 90%, 99%, and 99%, respectively. Only one patient received donor lymphocyte infusions (DLIs) for poor chimerism. Two patients died following disease progression despite 100% donor chimerism. The 3-year cumulative incidence of treatment-related mortality was 10% (95% CI, 2 to 17%). Overall survival and event-free-survival at 3-years were 87% (95% CI, 78 to 95%) and 80% (95% CI, 70 to 90%), respectively. The 6-month cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 7% (95% CI, 3 to 13%), while the 3-year cumulative incidence of chronic GVHD was 5% (95% CI, 0 to 11%). These results suggest that use of targeted busulfan, fludarabine and IV alemtuzumab offers a well-tolerated option for children with nonmalignant disorders to achieve sustained engraftment with a low incidence of GVHD.
Topics: Busulfan; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 32534101
DOI: 10.1016/j.bbmt.2020.06.004 -
Blood Advances Mar 2022We prospectively studied clofarabine-fludarabine-busulfan (CloFluBu)-conditioning in allogeneic hematopoietic cell therapy (HCT) for lymphoid and myeloid malignancies...
We prospectively studied clofarabine-fludarabine-busulfan (CloFluBu)-conditioning in allogeneic hematopoietic cell therapy (HCT) for lymphoid and myeloid malignancies and hypothesized that CloFluBu provides a less toxic alternative to conventional conditioning regimens, with adequate antileukemic activity. All patients receiving their first HCT, from 2011-2019, were included and received CloFluBu. The primary endpoint was event-free survival (EFS). Secondary endpoints were overall survival (OS), graft-versus-host disease (GvHD)-relapse-free survival (GRFS), treatment-related mortality (TRM), cumulative incidence of relapse (CIR), acute and chronic GvHD (aGvHD and cGvHD), and veno-occlusive disease (VOD). Cox proportional hazard and Fine and Gray competing-risk models were used for data analysis. One hundred fifty-five children were included: 60 acute lymphoid leukemia (ALL), 69 acute myeloid leukemia (AML), and 26 other malignancies (mostly MDS-EB). The median age was 9.7 (0.5 to 18.6) years. Estimated 2-year EFS was 72.0% ± 6.0 in ALL patients, and 62.4% ± 6.0 in AML patients. TRM in the whole cohort was 11.0% ± 2.6, incidence of aGvHD 3 to 4 at 6 months was 12.3% ± 2.7, extensive cGvHD at 2 years was 6.4% ± 2.1. Minimal residual disease-positivity prior to HCT was associated with higher CIR, both in ALL and AML. CloFluBu showed limited toxicity and encouraging EFS. CloFluBu is a potentially less toxic alternative to conventional conditioning regimens. Randomized prospective studies are needed.
Topics: Busulfan; Child; Clofarabine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Recurrence; Vidarabine
PubMed: 34781362
DOI: 10.1182/bloodadvances.2021005224