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1.
EJHaem ; 5(4): 757-767, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39157627

RESUMO

Relapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo-HSCT following fludarabine(≥100 mg/m2), busulfan (≥3.2 mg/kg) and melphalan (≥100 mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n = 171, MDS-IB-1 or 2 n = 44, CMML n = 6) with median age of 46 were enrolled in this study. The median follow-up was 507 days for survivors. The 2-year NRM, CIR, OS and DFS were 10.6% ± 2.2%, 14.8% ± 3.3%, 79.4% ± 3.7% and 74.6% ± 3.7%, respectively. In multivariate analyses, high HCT-CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p = 0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p = 0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p = 0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR = 7.92, 95%CI 1.05-60.03, p = 0.045; HR = 3.64, 95%CI 1.40-9.44, p = 0.008; respectively), while post-transplantation cyclophosphamide based graft-versus-host disease prophylaxis was associated with lower CIR (HR = 0.24 95%CI 0.11-0.54, p = 0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.

2.
Front Immunol ; 15: 1365946, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39131155

RESUMO

Introduction: Humanized mouse models to recapitulate human biological systems still have limitations, such as the onset of lethal graft-versus-host disease (GvHD), a variable success rate, and the low accessibility of total body irradiation (TBI). Recently, mice modified with the CD47-SIRPA axis have been studied to improve humanized mouse models. However, such trials have been rarely applied in NOD mice. In this study, we created a novel mouse strain, NOD-CD47nullRag2nullIL-2rγnull (RTKO) mice, and applied it to generate humanized mice. Methods: Four-week-old female NOD-Rag2nullIL-2rγnull (RID) and RTKO mice pre-conditioned with TBI or busulfan (BSF) injection were used for generating human CD34+ hematopoietic stem cell (HSC) engrafted humanized mice. Clinical signs were observed twice a week, and body weight was measured once a week. Flow cytometry for human leukocyte antigens was performed at intervals of four weeks or two weeks, and mice were sacrificed at 48 weeks after HSC injection. Results: For a long period from 16 to 40 weeks post transplantation, the percentage of hCD45 was mostly maintained above 25% in all groups, and it was sustained the longest and highest in the RTKO BSF group. Reconstruction of human leukocytes, including hCD3, was also most prominent in the RTKO BSF group. Only two mice died before 40 weeks post transplantation in all groups, and there were no life-threatening GvHD lesions except in the dead mice. The occurrence of GvHD has been identified as mainly due to human T cells infiltrating tissues and their related cytokines. Discussion: Humanized mouse models under all conditions applied in this study are considered suitable models for long-term experiments based on the improvement of human leukocytes reconstruction and the stable animal health. Especially, RTKO mice pretreated with BSF are expected to be a valuable platform not only for generating humanized mice but also for various immune research fields.


Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Camundongos Endogâmicos NOD , Camundongos Knockout , Condicionamento Pré-Transplante , Animais , Bussulfano/farmacologia , Humanos , Camundongos , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Células-Tronco Hematopoéticas/metabolismo , Feminino , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/deficiência , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/imunologia , Modelos Animais de Doenças , Irradiação Corporal Total
3.
PeerJ ; 12: e17691, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38978752

RESUMO

Background: Oligospermia is one of the most common reasons for male infertility which is troubling numerous couples of child-bearing age. This investigation scrutinizes the implications and mechanistic underpinnings of ursolic acid's effect on busulfan-induced oligospermia in mouse models. Methods: A singular intraperitoneal injection of busulfan at a dosage of 30 mg/kg induced oligospermia. Two weeks subsequent to this induction, mice were subjected to various dosages of ursolic acid (10, 30, and 50 mg/kg body weight, respectively) on a daily basis for four consecutive weeks. Following this treatment period, a meticulous analysis of epididymal sperm parameters, encompassing concentration and motility, was conducted using a computer-assisted sperm analysis system. The histopathology of the mice testes was performed utilizing hematoxylin and eosin staining, and the cytoskeleton regeneration of the testicular tissues was analyzed via immunofluorescent staining. Serum hormone levels, including testosterone, luteinizing hormone, and follicle-stimulating hormone, as well as reactive oxygen species levels (inclusive of reactive oxygen species and malondialdehyde), were gauged employing specific enzyme-linked immunosorbent assay kits. Differentially expressed genes of testicular mRNA between the oligospermia-induced group and the various ursolic acid treatment groups were identified through RNA sequencing analysis. Results: The results revealed that a dosage of 50 mg/kg ursolic acid treatment could increase the concentration of epididymal sperm in oligospermia mice, promote the recovery of testicular morphology, regulate hormone levels and ameliorate oxidative damage. The mechanism research results indicated that ursolic acid increased the expression level of genes related to motor proteins in oligospermia mice.


Assuntos
Bussulfano , Oligospermia , Testículo , Triterpenos , Ácido Ursólico , Animais , Masculino , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Oligospermia/induzido quimicamente , Oligospermia/tratamento farmacológico , Camundongos , Testículo/efeitos dos fármacos , Testículo/patologia , Testículo/metabolismo , Modelos Animais de Doenças , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Espermatozoides/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Testosterona/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Epididimo/efeitos dos fármacos , Epididimo/patologia , Epididimo/metabolismo
4.
Drug Chem Toxicol ; : 1-14, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38948945

RESUMO

Gallic acid (GAL), rutin (RUT), and quercetin (QUE) are common antioxidant agents in fruits and vegetables with intriguing pharmacological effects. In the present study, we compared the therapeutic outcomes of GAL + QUE in comparison with GAL + RUT co-treatment in a busulfan (BUS) model of testicular injury in Wistar rats. BUS (4 mg kg-1 body weight (b.w) was injected intraperitoneally daily for 4 days. GAL + RUT or GAL + QUE (20 mg kg-1 b. w) was delivered by oral gavage for 52 days. Examination of the testes of BUS-treated rats both biochemically and under light microscopy revealed an increased level of lipid peroxidation, DNA fragmentation, glutathione-S-transferase, lactate dehydrogenase, gamma-glutamyl transpeptidase, alkaline phosphatase and acid phosphatase with a concomitant decrease in the level of antioxidants: glutathione, ascorbic acid, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, suggesting testicular injury. Tissue sections confirmed the testicular injury-induced by BUS, including diminished spermatogenesis score index, tubular diameter, gonado-somatic index, testis weight, epithelia thickness and higher percentage of aberrant tubules. GAL + QUE co-administration had better recovery effects than GAL + RUT on the biochemical markers and protected against BUS-induced testicular damage. GAL + QUE treatment regimen has better capacity to maintain the antioxidant capacity of the testes and is more potent at reducing BUS-induced oxidative damage compared to GAL + RUT.

5.
Artigo em Inglês | MEDLINE | ID: mdl-39067789

RESUMO

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31, 2014 and November 12, 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1 + 2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval [95% CI]: 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, P < .001). Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

6.
Br J Haematol ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39049594

RESUMO

Reduced-intensity conditioning regimens are commonly used in allogeneic haematopoietic cell transplantation for non-Hodgkin lymphoma (NHL); however, the optimal regimen remains unknown. In this study, the outcomes of adult patients with NHL who received fludarabine plus reduced-dose busulfan (6.4 mg/kg; Flu/Bu2) (n = 286) and fludarabine plus low-dose melphalan (80 or 100 mg/m2; Flu/Mel80-100) (n = 283) between January 2009 and December 2020 were compared using Japanese registry data. The primary end-point was the 5-year overall survival (OS). The 5-year OS was 53.8% (95% CI, 47.6-59.6) and 42.4% (95% CI, 35.6-49.0) in the Flu/Bu2 and Flu/Mel80-100 groups respectively (p = 0.030). After inverse probability of treatment weighting adjustment, the adjusted HR of Flu/Bu2 compared with Flu/Mel80-100 group for 5-year OS was 0.77 (95% CI, 0.60-0.99, p = 0.046), 0.97 (95% CI, 0.78-1.21, p = 0.798) for 5-year progression-free survival, 0.65 (95% CI, 0.45-0.94, p = 0.022) for 5-year cumulative risk of non-relapse mortality and 1.25 (95% CI, 0.95-1.64, p = 0.115) for 5-year cumulative risk of relapse. In this study, patients with NHL who received Flu/Bu2 were associated with better OS and lower non-relapse mortality than those who received Flu/Mel80-100.

7.
Int J Mol Sci ; 25(12)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38928028

RESUMO

Busulfan, an indispensable medicine in cancer treatment, can cause serious reproductive system damage to males as a side effect of its otherwise excellent therapeutic results. Its widespread use has also caused its accumulation in the environment and subsequent ecotoxicology effects. As a Chinese medicine, Wulingzhi (WLZ) has the effects of promoting blood circulation and improving female reproductive function. However, the potential effects of WLZ in male reproduction and in counteracting busulfan-induced testis damage, as well as its probable mechanisms, are still ambiguous. In this study, busulfan was introduced in a mouse model to evaluate its production of the testicular damage. The components of different WLZ extracts were compared using an untargeted metabolome to select extracts with greater efficacy, which were further confirmed in vivo. Here, we demonstrate abnormal spermatogenesis and low sperm quality in busulfan-injured testes. The WLZ extracts showed a strong potential to rehabilitate the male reproductive system; this effect was more prominent in room-temperature extracts. Additionally, both water and ethanol WLZ extracts at room temperature alleviated various busulfan-induced adverse effects. In particular, WLZ recovered spermatogenesis, re-activated arginine biosynthesis, and alleviated the increased oxidative stress and inflammation in the testis, ultimately reversing the busulfan-induced testicular injury. Collectively, these results suggest a promising approach to protecting the male reproductive system from busulfan-induced adverse side effects, as well as those of other similar anti-cancer drugs.


Assuntos
Arginina , Bussulfano , Medicamentos de Ervas Chinesas , Espermatogênese , Testículo , Masculino , Animais , Bussulfano/efeitos adversos , Bussulfano/toxicidade , Camundongos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Espermatogênese/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo
8.
Ann Hematol ; 103(8): 3105-3119, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38829409

RESUMO

Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of anti-thymocyte globulin (ATG) based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG-based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in older or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG-based haploidentical HSCT. We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30 mg/m²/kg 6 days combined with busulfan 3.2 mg/kg 2 days (Bu2) or 3 days (Bu3). ATG-Fresenius (ATG-F) was administered 10 mg/kg in total, ATG-thymoglobulin (ATG-T) was administered 6 mg/kg in total. The median age of patients in the entire cohort was 60 (32-67) years with a median follow-up of 496 (83-2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. A total of 32 patients underwent Bu2 RIC haplo-HSCT and 31 patients were treated with Bu3 RIC haplo-HSCT. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8 - 85.1%) and 61.4% (95% CI, 48.8 - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8% (95% CI, 4.8 - 19.6%) and 9.7% (95% CI, 0.0 - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9 - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5 - 33.7%) and 11.6% (95% CI, 2.2 - 21.9%) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5-85.3%) in Bu2 and 85.5%(95% CI:73.0-100%) in Bu3 group respectively(P = 0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0-74.8%) in Bu2 and 72.6% (95% CI:55.5-95.5%) in Bu3 group respectively (P = 0.045). The 2-year IR of Bu2 group was significantly higher than Bu3 group (P = 0.045). However, the 2-year NRM were not significantly different between Bu2 and Bu3 group(P > 0.05). In multivariable analysis, RIC regimen of Bu3 had superior OS and DFS than Bu2 group respectively [HR 0.42, 95% CI 0.18-0.98; P = 0.044; HR 0.34, 95% CI 0.14-0.86; P = 0.022]. Besides, RIC regimen of Bu3 had lower IR than Bu2 group [HR 0.34, 95% CI 0.13-0.89; P = 0.029]. The RIC regimen of ATG-based haploidentical HSCT is a safe and effective treatment option for patients who are older or have poor functional status. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in OS and DFS, thus providing more favorable post-transplantation clinical outcomes.


Assuntos
Soro Antilinfocitário , Bussulfano , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Vidarabina , Humanos , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Feminino , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Estudos Retrospectivos , Idoso , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/mortalidade , Transplante Haploidêntico/métodos , Taxa de Sobrevida
9.
Poult Sci ; 103(8): 103890, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38870613

RESUMO

Generation of transgenic birds can be achieved by temporal suppression of endogenous spermatogenesis in males prior to primordial germ cell implantation. One of many established methods to induce male sterility is the intraperitoneal injection of busulfan, an alkylating agent. Nevertheless, the use of busulfan injections, which may also affect hematopoietic stem cells, carries the risk of potential lethality in animals. Given their safety and non-toxic nature, it has been demonstrated that intratesticular busulfan injections in mammals are less effective than intraperitoneal injections. This study aimed to compare, for the first time, the sterility and toxicity effects of intraperitoneal vs. intratesticular busulfan injections in quail and chickens. Our experimental design involved a previously established single intraperitoneal busulfan injection of 40 mg/kg of body weight (BW). In quail, busulfan was then administered intratesticularly at 3 different concentrations (6, 12, and 20 mg/kg BW), while in chickens, the working concentration was 20 mg/kg BW. We found that a single intraperitoneal busulfan injection of 40 mg/kg of BW resulted in 100% mortality in the treated roosters. In quails, however, this concentration only caused a temporary suppression of fertility for a 15-d period. Moreover, we found that a higher dose of intratesticular injection of busulfan is required to suppress spermatogenesis in quail (20 mg/kg BW) compared to mammals (4 mg/kg BW). Following these findings, we further confirmed that intratesticular injection of 20 mg/kg BW busulfan into roosters did not affect their overall viability. However, it induced a temporary state of male sterility, consistent with the effects observed with intraperitoneal injections. Hence, our data demonstrate that quail and chicken respond differently to busulfan administration. Furthermore, the present study provides evidence that direct injection into the rooster testes causes less physiological stress than intraperitoneal injection.


Assuntos
Bussulfano , Galinhas , Coturnix , Espermatogênese , Testículo , Animais , Bussulfano/administração & dosagem , Masculino , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Injeções Intraperitoneais/veterinária , Galinhas/fisiologia , Coturnix/fisiologia , Injeções/veterinária , Infertilidade Masculina/veterinária , Infertilidade Masculina/induzido quimicamente
10.
Lipids Health Dis ; 23(1): 180, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862993

RESUMO

BACKGROUND: The management of male infertility continues to encounter an array of challenges and constraints, necessitating an in-depth exploration of novel therapeutic targets to enhance its efficacy. As an eight-carbon medium-chain fatty acid, octanoic acid (OCA) shows promise for improving health, yet its impact on spermatogenesis remains inadequately researched. METHODS: Mass spectrometry was performed to determine the fatty acid content and screen for a pivotal lipid component in the serum of patients with severe spermatogenesis disorders. The sperm quality was examined, and histopathological analysis and biotin tracer tests were performed to assess spermatogenesis function and the integrity of the blood-testis barrier (BTB) in vivo. Cell-based in vitro experiments were carried out to investigate the effects of OCA administration on Sertoli cell dysfunction. This research aimed to elucidate the mechanism by which OCA may influence the function of Sertoli cells. RESULTS: A pronounced reduction in OCA content was observed in the serum of patients with severe spermatogenesis disorders, indicating that OCA deficiency is related to spermatogenic disorders. The protective effect of OCA on reproduction was tested in a mouse model of spermatogenic disorder induced by busulfan at a dose 30 mg/kg body weight (BW). The mice in the study were separated into distinct groups and administered varying amounts of OCA, specifically at doses of 32, 64, 128, and 256 mg/kg BW. After evaluating sperm parameters, the most effective dose was determined to be 32 mg/kg BW. In vivo experiments showed that treatment with OCA significantly improved sperm quality, testicular histopathology and BTB integrity, which were damaged by busulfan. Moreover, OCA intervention reduced busulfan-induced oxidative stress and autophagy in mouse testes. In vitro, OCA pretreatment (100 µM) significantly ameliorated Sertoli cell dysfunction by alleviating busulfan (800 µM)-induced oxidative stress and autophagy. Moreover, rapamycin (5 µM)-induced autophagy led to Sertoli cell barrier dysfunction, while OCA administration exerted a protective effect by alleviating autophagy. CONCLUSIONS: This study demonstrated that OCA administration suppressed oxidative stress and autophagy to alleviate busulfan-induced BTB damage. These findings provide a deeper understanding of the toxicology of busulfan and a promising avenue for the development of novel OCA-based therapies for male infertility.


Assuntos
Autofagia , Barreira Hematotesticular , Bussulfano , Caprilatos , Estresse Oxidativo , Células de Sertoli , Espermatogênese , Masculino , Animais , Barreira Hematotesticular/efeitos dos fármacos , Barreira Hematotesticular/metabolismo , Bussulfano/efeitos adversos , Caprilatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Humanos , Espermatogênese/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/patologia , Testículo/efeitos dos fármacos , Testículo/patologia , Testículo/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Adulto
12.
Cancer Med ; 13(10): e7292, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38752476

RESUMO

INTRODUCTION: Type of conditioning regimen impacts the outcome of patients who undergo allogeneic HSCT since graft versus host disease (GVHD), infections, regimen related toxicities (RRT) are important causes of post-transplant mortality. Despite the RRT profile of busulfan, it is frequently used worldwide. Treosulfan has advantages in terms of dose of administration, lower incidence of sinusoidal obstruction syndrome and lower neurotoxicity. We retrospectively investigated outcomes of patients who underwent allogeneic HSCT with treosulfan or busulfan based conditioning regimens in our institution. METHODS: Treosulfan was administered to 94 patients while 85 patients received busulfan. Our outcomes were RRT, chronic and acute GVHD, relapse related mortality (RRM), non-relapse mortality, and fungal infection. The clinical follow up data, regarding the primary and secondary endpoints of our study, of the patients who received treosulfan or busulfan based conditioning regimens were statistically analyzed. RESULTS: The median follow-up was 14 months for the treosulfan group while it was 11 months for the busulfan group (p = 0.16). RRT was 11.7% and 7.1% for treosulfan and busulfan respectively. The incidence of extensive chronic GVHD was less frequent in the treosulfan group compared to the busulfan group (15.7% vs. 32.1%) (p < 0.001). The incidence of acute GVHD (Grade 3 or higher) was 32.2% in the treosulfan group while it was 31.6% in the busulfan group. The RRM was 17% in the treosulfan group while it was 34% in the busulfan group. The non-relapse mortality was 35.5% and 29.4% in the treosulfan group and in the busulfan group respectively (p = 0.962). CONCLUSION: Treosulfan, with a lower RRM, lower chronic GVHD incidence and with a similar RRT profile appears to be a safe alternative to busulfan.


Assuntos
Bussulfano , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Transplante Homólogo , Humanos , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Bussulfano/efeitos adversos , Bussulfano/administração & dosagem , Condicionamento Pré-Transplante/métodos , Feminino , Masculino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Pessoa de Meia-Idade , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/epidemiologia , Estudos Retrospectivos , Adulto Jovem , Adolescente , Resultado do Tratamento , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos
13.
Eur J Haematol ; 113(1): 110-116, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38566462

RESUMO

OBJECTIVES: Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. METHODS: We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. RESULTS: The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. CONCLUSION: Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.


Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos , Condicionamento Pré-Transplante , Transplante Homólogo , Vidarabina , Humanos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Bussulfano/efeitos adversos , Bussulfano/administração & dosagem , Estudos Retrospectivos , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Agonistas Mieloablativos/administração & dosagem , Irradiação Corporal Total/efeitos adversos , Adulto Jovem , Seguimentos , Medula Óssea/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Idoso , Adolescente
14.
Ann Hematol ; 103(6): 2165-2168, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38584216

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.


Assuntos
Bussulfano , Células Dendríticas , Transplante de Células-Tronco Hematopoéticas , Tiotepa , Condicionamento Pré-Transplante , Vidarabina , Humanos , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Condicionamento Pré-Transplante/métodos , Células Dendríticas/patologia , Tiotepa/administração & dosagem , Tiotepa/uso terapêutico , Masculino , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/patologia , Feminino , Transplante Homólogo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aloenxertos
15.
Theranostics ; 14(6): 2622-2636, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38646657

RESUMO

Rationale: In recent years, nicotinamide adenine dinucleotide (NAD+) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and animal models. However, whether and how Npre plays a role in the male reproductive disorder has not been fully clarified. Methods: In the present study, a busulfan-induced non-obstructive azoospermic mouse model was used, and Npre was administered for five weeks following the drug injection, with the objective of reinstating spermatogenesis and fertility. Initially, we assessed the NAD+ level, germ cell types, semen parameters and sperm fertilization capability. Subsequently, testis tissues were examined through RNA sequencing analysis, ELISA, H&E, immunofluorescence, quantitative real-time PCR, and Western blotting techniques. Results: The results indicated that Npre restored normal level of NAD+ in blood and significantly alleviated the deleterious effects of busulfan (BU) on spermatogenesis, thereby partially reestablishing fertilization capacity. Transcriptome analysis, along with recovery of testicular Fe2+, GSH, NADPH, and MDA levels, impaired by BU, and the fact that Fer-1, an inhibitor of ferroptosis, restored spermatogenesis and semen parameters close to CTRL values, supported such possibility. Interestingly, the reduction in SIRT2 protein level by the specific inhibitor AGK2 attenuated the beneficial effects of Npre on spermatogenesis and ferroptosis by affecting PGC-1α and ACLY protein levels, thus suggesting how these compounds might confer spermatogenesis protection. Conclusion: Collectively, these findings indicate that NAD+ protects spermatogenesis against ferroptosis, probably through SIRT2 dependent mechanisms. This underscores the considerable potential of Npre supplementation as a feasible strategy for preserving or restoring spermatogenesis in specific conditions of male infertility and as adjuvant therapy to preserve male fertility in cancer patients receiving sterilizing treatments.


Assuntos
Bussulfano , Ferroptose , NAD , Sirtuína 2 , Espermatogênese , Animais , Bussulfano/farmacologia , Masculino , Espermatogênese/efeitos dos fármacos , Camundongos , NAD/metabolismo , Ferroptose/efeitos dos fármacos , Sirtuína 2/metabolismo , Sirtuína 2/genética , Modelos Animais de Doenças , Testículo/metabolismo , Testículo/efeitos dos fármacos , Azoospermia/tratamento farmacológico , Azoospermia/metabolismo , Azoospermia/induzido quimicamente
16.
Pediatr Transplant ; 28(3): e14728, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38600717

RESUMO

BACKGROUND: Although neurotoxicity is a major adverse event associated with busulfan, little information is available regarding the association between drug interactions and neurological symptoms during busulfan-based regimens. This study evaluated the association between prophylactic echinocandins and neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation. METHODS: We retrospectively included consecutive patients who administered intravenous busulfan as a conditioning regimen at our facility between 2007 and 2022. Prophylactic echinocandin use was defined as the use of an echinocandin antifungal drug to prevent invasive fungal disease in SCT recipients. The primary outcome was the incidence of neurological complications within 7 days of busulfan initiation and was compared between the echinocandin group (patients received prophylactic echinocandin) and nonechinocandin group (patients received prophylactic antifungal drugs other than echinocandin and those without antifungal prophylaxis). RESULTS: Among the 59 patients included in this study, the incidence of neurological complications in the echinocandin (n = 26) and nonechinocandin groups (n = 33) was 30.8% and 63.6%, respectively. We observed a negative association between prophylactic echinocandin use and the development of neurological complications after adjusting for the propensity score for receiving prophylactic echinocandins (adjusted odds ratio 0.294, 95% confidence interval 0.090 to 0.959). We observed a lower incidence of neurological complications in the echinocandin group than in the nonechinocandin group. CONCLUSION: Our results suggested that the choice of antifungal prophylaxis is associated with busulfan neurotoxicity.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Nervoso , Humanos , Bussulfano/efeitos adversos , Estudos Retrospectivos , Antifúngicos/uso terapêutico , Equinocandinas/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco , Doenças do Sistema Nervoso/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/etiologia
17.
J Toxicol Sci ; 49(4): 139-149, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38556351

RESUMO

Busulfan is an anticancer drug known to cause serious damage to seminiferous tubules in the testes and deplete germ cells in human and animal models. The testicular artery is anastomosed with deferential and cremasteric arteries and is divided into capsular arteries, which give rise to the centripetal arteries and then recurrent arteries. The arterial blood in the testicular tissue is supplied by such a consequent system of arterial vessels, in order from the peripheral to the central area. As anticancer drugs are generally distributed throughout the whole body via the bloodstream and the running and distribution of arteries differ among the testicular areas, we hypothesized that the efficacy of busulfan differs in different testicular areas, particularly between the central and peripheral areas. In this study, busulfan was intraperitoneally injected at 40 mg/kg body weight into C57BL/6J male mice. After 28 days, in busulfan-treated mice, the diameters of seminiferous tubules were significantly higher in the central than in the peripheral area of the testes. The seminiferous tubular areas also significantly decreased in the peripheral areas compared with the central areas. The number of germ cells per seminiferous tubule was significantly higher in the central than in the peripheral area. Sertoli cell nuclei were detached into the lumen in the peripheral area. The number of Leydig cells was significantly lower in the peripheral areas. These data suggest that the effects of busulfan differ between the central and peripheral areas of the testis at 4 weeks after busulfan administration.


Assuntos
Bussulfano , Testículo , Masculino , Animais , Humanos , Camundongos , Bussulfano/toxicidade , Espermatogênese , Camundongos Endogâmicos C57BL , Túbulos Seminíferos
18.
Front Immunol ; 15: 1369243, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469307

RESUMO

Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in ELANE, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with ELANE-mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Neutropenia , Neutropenia/congênito , Humanos , Criança , Transplante de Medula Óssea/efeitos adversos , Síndrome Congênita de Insuficiência da Medula Óssea , Bussulfano/uso terapêutico , Bussulfano/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Irmãos , Estudos Prospectivos , Neutropenia/complicações , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/uso terapêutico
19.
Oncotarget ; 15: 220-231, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38484153

RESUMO

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.


Assuntos
Bussulfano , Leucemia Mieloide Aguda , Sulfonamidas , Vidarabina/análogos & derivados , Humanos , Bussulfano/farmacologia , Tiotepa/uso terapêutico , Cladribina/farmacologia , Leucemia Mieloide Aguda/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Combinação de Medicamentos , Linhagem Celular Tumoral , Apoptose
20.
Drug Des Devel Ther ; 18: 871-879, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38524879

RESUMO

Purpose: Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Patients and methods: Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Results: Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. Conclusion: While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.


Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Bussulfano/farmacocinética , Bussulfano/toxicidade , Infusões Intravenosas , Transplante Homólogo , Condicionamento Pré-Transplante
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