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Transplantation and Cellular Therapy Mar 2021The overall objective of allogeneic hematopoietic cell transplantation (HCT) in patients with non-malignant conditions involves replacing a dysfunctional or absent cell...
The overall objective of allogeneic hematopoietic cell transplantation (HCT) in patients with non-malignant conditions involves replacing a dysfunctional or absent cell or gene product for disease correction. It is unclear whether lower busulfan exposure may be sufficient in this population to facilitate durable myeloid engraftment and limit toxicity. Given that neither the ideal level of mixed myeloid chimerism for specific non-malignant diseases nor how to condition a patient to achieve stable mixed myeloid chimerism is fully known, we sought to analyze the relationships among busulfan exposure, myeloid chimerism, and outcomes in patients with non-malignant conditions receiving busulfan as a part of combination pretransplant conditioning at our institution. This was a single-center, retrospective study including pediatric patients with a variety of non-malignant disorders who underwent allogeneic HCT at the University of California San Francisco Benioff Children's Hospital from March 2007 to June 2018. The busulfan cumulative area under the curve (cAUC) was estimated using a validated population pharmacokinetic model and nonlinear mixed effects modeling. Median busulfan cAUC for all patients was 70 mg·h/L (range, 53 to 108). All of the 29 patients with a busulfan cAUC of ≥70 mg·h/L achieved long-term disease correction with full or stable mixed (>20%) myeloid chimerism, compared to 78.5% (22/28) of patients with a cAUC of <70 mg·h/L (P = .01). Overall ksurvival was evaluated up to 3 years and was identical in patients with busulfan cAUC < 70 mg·h/L and patients with busulfan cAUC ≥70 mg·h/L (96% versus 93%; P = .92). Only three patients died, at days 65, 164 and 980 days post-HCT. Severe busulfan-related toxicities and graft-versus-host-disease (GVHD) were rare, with veno-occlusive disease occurring in four patients (7%), acute respiratory distress syndrome in three patients (5%), and GVHD in five patients (9%). These results demonstrate excellent outcomes and extremely low rates of toxicity across our entire cohort. Based on the results of this study, we recommend a busulfan exposure target of 75 mg·h/L (range, 70 to 80) in all non-malignant patients receiving allogeneic HCT to ensure optimal exposure for achievement of high-level stable myeloid chimerism.
Topics: Busulfan; Child; Chimerism; Humans; Retrospective Studies; San Francisco; Transplantation Conditioning
PubMed: 33781528
DOI: 10.1016/j.jtct.2020.12.005 -
Thorax Nov 1969A 61-year-old man with chronic myeloid leukaemia was treated with busulphan (Myleran). After receiving 1 g. of this drug over a period of 20 months he became dyspnoeic...
A 61-year-old man with chronic myeloid leukaemia was treated with busulphan (Myleran). After receiving 1 g. of this drug over a period of 20 months he became dyspnoeic and developed crepitations in the lungs. Two months later radiographs of the chest revealed peri-hilar infiltrates and subsequently diffuse mottling throughout both lungs. Lung function tests showed a gross impairment of the transfer factor to a quarter of the predicted normal. At necropsy the lungs showed a striking proliferation of granular pneumocytes, many of which had disintegrated to produce intra-alveolar debris, some of which showed organization by fibrous tissue. There was associated interstitial pulmonary fibrosis. Electron microscopy confirmed the desquamated alveolar cells to be type II (granular) pneumocytes containing characteristic lamellar bodies. Many of these osmiophilic bodies, believed to be the source of pulmonary surfactant, had been liberated into the alveolar spaces, with the formation of phospholipid myelin figures and lattices. We think that the basic pathology of busulphan lung is a chemically induced alveolitis with proliferation of granular pneumocytes followed by fibrosis of alveolar walls and intra-alveolar contents.
Topics: Busulfan; Humans; Leukemia, Myeloid; Lung; Lung Diseases; Male; Microscopy, Electron; Middle Aged; Pulmonary Alveoli; Pulmonary Fibrosis; Radiography; Respiratory Function Tests; Spirometry
PubMed: 5260190
DOI: 10.1136/thx.24.6.639 -
Transplantation and Cellular Therapy Apr 2022Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation... (Observational Study)
Observational Study
Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation.
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
Topics: Administration, Intravenous; Busulfan; Child; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Transplantation Conditioning; Young Adult
PubMed: 35065280
DOI: 10.1016/j.jtct.2022.01.013 -
Biology of Blood and Marrow... May 2019Patients with high-risk myeloproliferative neoplasms (MPNs), and in particular myelofibrosis (MF), can be cured only with allogeneic hematopoietic stem cell...
Patients with high-risk myeloproliferative neoplasms (MPNs), and in particular myelofibrosis (MF), can be cured only with allogeneic hematopoietic stem cell transplantation (HSCT). Because MPNs and JAK2-mutated cells show genomic instability, stalled replication forks, and baseline DNA double-strand breaks, DNA repair inhibition with poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors represents a potential novel therapy. Because the alkylating agent busulfan is integral in conditioning regimens for HSCT and leads to stalled replication forks through DNA strand cross-linking, we hypothesized that PARP inhibition with veliparib in combination with busulfan may lead to synergistic cytotoxicity in MPN cells. We first treated 2 MPN cell lines harboring the JAK2 mutation (SET2 and HEL) with veliparib at increasing concentrations and measured cell proliferation. SET2 and HEL cells were relatively sensitive to veliparib (IC of 11.3 μM and 74.2 μM, respectively). We next treated cells with increasing doses of busulfan in combination with 4 μM veliparib and found that the busulfan IC decreased from 27 μM to 4 μM in SET2 cells and from 45.1 μM to 28.1 μM in HEL cells. The mean combination index was .55 for SET2 cells and .40 for HEL cells. Combination treatment of SET2 cells caused G2M arrest in 53% of cells, compared with 30% with veliparib alone and 35% with busulfan alone. G2M arrest was associated with activation of the ATR-Chk1 pathway, as shown by an immunofluorescence assay for phosphorylated Chk1 (p-Chk1). We then tested in vivo the effect of combined low doses of busulfan and veliparib in a JAK2 MPN-AML xenotransplant model. Vehicle- and veliparib-treated mice had similar median survival of 39 and 40 days, respectively. Combination treatment increased median survival from 47 days (busulfan alone) to 50 days (P = .02). Finally, we tested the combined effect of busulfan and veliparib on CD34 cells obtained from the bone marrow or peripheral blood of 5 patients with JAK2-mutated and 2 patients with CALR-mutated MF. MF cells treated with the combination of veliparib and busulfan showed reduced colony formation compared with busulfan alone (87% versus 68%; P = .001). In contrast, treatment of normal CD34 cells with veliparib did not affect colony growth. Here we show that in vivo confirmation that treatment with the PARP-1 inhibitor veliparib and busulfan results in synergistic cytotoxicity in MPN cells. Our data provide the rationale for testing novel pretransplantation conditioning regimens with combinations of PARP-1 inhibition and reduced doses of alkylators, such as busulfan and melphalan, for high-risk MPNs or MPN-derived acute myelogenous leukemia.
Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Busulfan; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Heterografts; Humans; Mice; Myeloproliferative Disorders; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 30615982
DOI: 10.1016/j.bbmt.2018.12.841 -
Transplantation and Cellular Therapy Feb 2022Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable...
Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable description of busulfan PK and optimization of exposure, which leads to improvement of event-free survival after HCT. Prior busulfan popPK analysis has been limited by small numbers in patients with inherited metabolic disorders (IMD). The primary objective was to characterize population PK of busulfan in a large cohort of children and young adults undergoing HCT for IMD. PopPK analysis of busulfan drug concentrations was performed using data from 78 patients with IMD who received intravenous busulfan (every 24 hours, 4 doses) as part of pretransplantation combination chemotherapy. The final model for busulfan drug clearance was used to estimate individual doses aimed to achieve a target cumulative area under the curve (cAUC) of 80 to 100 mg · h/L. We then compared the probability of cAUC within the range of 80 to 100 mg · h/L by the developed dosing regimen versus conventional regimen. A 1-compartment, linear elimination model best described the PK of busulfan. Significant covariates demonstrated to affect busulfan clearance included total body weight and the time (in days) from busulfan infusion start. The probability of target cAUC attainment by the developed dosing versus the conventional dosing were 47% versus 43% for body weight <12 kg, and 48% versus 36% for body weight ≥12 kg. We described population PK of intravenous busulfan in a large IMD cohort. The proposed dosing regimen based on the developed model can improve the target cAUC attainment of busulfan for IMD.
Topics: Body Weight; Busulfan; Child; Hematopoietic Stem Cell Transplantation; Humans; Metabolic Diseases; Transplantation Conditioning; Young Adult
PubMed: 34883294
DOI: 10.1016/j.jtct.2021.11.018 -
Biology of Blood and Marrow... Jan 2020The high cost of healthcare in the United States has not been consistently associated with improved health outcomes or quality of care, necessitating a focus on... (Clinical Trial)
Clinical Trial Comparative Study
The high cost of healthcare in the United States has not been consistently associated with improved health outcomes or quality of care, necessitating a focus on value-based care. We identified busulfan dosing frequency during allogeneic hematopoietic cell transplantation (HCT) conditioning as a potential target for optimization. To improve patient convenience and to decrease the cost of busulfan-based conditioning regimens, our institution changed busulfan dose frequency from every 6 hours (q6h) to once-daily (q24h). We compared costs and patient outcomes between these 2 dosing schedules. In June 2017, our institution transitioned from q6h to q24h busulfan dosing. We compared patients who received busulfan/cyclophosphamide conditioning regimens (BU/CY) for allogeneic HCT in the year before the dosing change (q6h cohort) and those who did so in the year after the dosing change (q24h cohort). The primary outcomes were differences in cost, day +90 mortality, and day +90 relapse. Between June 1, 2016, and June 1, 2018, 104 patients (median age 49 years; range, 20 to 63 years) received BU/CY before allogeneic HCT. Fifty-nine patients (57%) received q6h busulfan and 45 (43%) received q24h busulfan. There were fewer men in the q24h busulfan cohort compared with the q6h busulfan cohort (42% versus 64%; P = .024), but there were no other significant differences between the groups. There was an average annual cost savings of $19,990 per patient with q24h busulfan compared with q6h busulfan, and an annual busulfan cost savings of $899,550. There was a significantly lower day +90 mortality in the q24h busulfan cohort compared to the q6h busulfan cohort (0% versus 10%; P = .028). There were no significant differences in relapse at day +90 or in hospital length of stay. Our data indicate that i.v. busulfan dosing for allogeneic HCT conditioning is a target for improved value-based care. At our institution, patients who received q24h busulfan dosing had similar or superior outcomes compared with those receiving q6h dosing, with an average annual cost reduction of $19,990 per patient and an overall annual reduction in busulfan cost of approximately $900,000. These data support the adoption of q24h i.v. busulfan dosing as a standard of care to improve value-based care in allogeneic HCT.
Topics: Administration, Intravenous; Adult; Allografts; Busulfan; Costs and Cost Analysis; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Retrospective Studies; Survival Rate
PubMed: 31525492
DOI: 10.1016/j.bbmt.2019.09.008 -
Biology of Blood and Marrow... Apr 2020This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days)...
Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa, Busulfan, and Fludarabine (TBF): A Retrospective Study.
This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.
Topics: Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Retrospective Studies; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 31875522
DOI: 10.1016/j.bbmt.2019.12.725 -
BMC Pediatrics Apr 2020Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial.
METHODS
Research on pertinent literature was carried out at PubMed, EMBASE, Web of science, the Cochrane Library and ClinicalTrials.gov. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 μM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events.
RESULTS
Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 μM × min, the mean AUC value of < 900 μM × min significantly increased the incidence of graft failure (RR = 3.666, 95% CI: 1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC < 1350 μM × min (RR = 0.370, 95% CI: 0.205-0.666) and < 1500 μM × min (RR = 0.409, 95% CI: 0182-0.920).
CONCLUSIONS
In children, Bu mean AUC above the cut-off value of 900 μM × min (after every 6-h dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 μM × min were associated with increased risk of VOD, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.
Topics: Adolescent; Busulfan; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Infant; Prospective Studies; Transplantation Conditioning
PubMed: 32312247
DOI: 10.1186/s12887-020-02028-6 -
Clinical and Translational Science Dec 2023Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite...
Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ-glutamyldehydroalanylglycine, which is too unstable to be quantitated in vivo. We sought to evaluate if pre-graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non-relapse mortality, and neutrophil nadir. In pre-graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1-oxide, sulfolane, and 3-hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre-graft samples, busulfan and THT+ could not be detected. THT 1-oxide, sulfolane, and 3-hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre-graft samples; their concentrations were not associated with clinical outcomes. Four pre-graft EMCs were statistically significantly associated with the neutrophil nadir. The pre-graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre-graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre-graft plasma from allogeneic HCT recipients.
Topics: Humans; Busulfan; Transplant Recipients; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Glutathione; Allografts
PubMed: 37749994
DOI: 10.1111/cts.13651 -
Transplantation and Cellular Therapy Jul 2021One hundred and sixty-one patients underwent haploidentical stem cell transplantation (haploSCT) with thiotepa, busulfan, and fludarabine conditioning followed by...
Combining Three Different Pretransplantation Scores Improves Predictive Value in Patients after Haploidentical Stem Cell Transplantation with Thiotepa, Busulfan, and Fludarabine Conditioning and Post-Transplantation Cyclophosphamide.
One hundred and sixty-one patients underwent haploidentical stem cell transplantation (haploSCT) with thiotepa, busulfan, and fludarabine conditioning followed by post-transplantation cyclophosphamide (PTCy) (on days +3 and +4) and tacrolimus as graft-versus-host disease prophylaxis. Forty-two percent of patients had a high or very high revised Disease Risk Index (rDRI), 55% had an European Society for Blood and Marrow Transplantation risk score (EBMT-RS) ≥4, and 36% had an age-adjusted Hematopoietic Cell Transplant Comorbidity Index (HCT-CI-age) score ≥3. Each of these was considered an unfavorable score. Using the pretransplantation unfavorable scores that had an independent impact on each transplantation outcome studied in multivariate analysis allowed for better stratification of patient outcomes. Thus, the 3-year overall survival (OS) in patients with 0, 1, 2, and 3 unfavorable scores was 86%, 56%, 36%, and 24%, respectively. Nonrelapse mortality (NRM) was negatively impacted by the EBMT-RS and the HCT-CI-age score (3-year NRM in patients with 0, 1, and 2 unfavorable scores was 12%, 33%, and 43%, respectively), whereas the EBMT-RS and the rDRI had an impact on the 3-year relapse incidence (8%, 18%, and 41% in patients with 0, 1, and 2 unfavorable scores, respectively). In conclusion, our study shows that combining 2 or 3 of these well-defined pretransplantation scores improves the ability to predict transplantation outcomes in the setting of haploSCT with PTCy.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 33775908
DOI: 10.1016/j.jtct.2021.03.021