RESUMEN

INTRODUCTION: Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. METHODS: We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. RESULTS: The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. CONCLUSION: The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Busulfano , Trasplante de Células Madre Hematopoyéticas , Melfalán , Sarcoma de Ewing , Trasplante Autólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/terapia , Busulfano/administración & dosificación , Busulfano/efectos adversos , Niño , Adolescente , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melfalán/administración & dosificación , Melfalán/efectos adversos , Melfalán/uso terapéutico , Masculino , Femenino , Factores de Edad , Adulto , Etopósido/administración & dosificación , Etopósido/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Vincristina/efectos adversos , Vincristina/administración & dosificación , Vincristina/uso terapéutico , Preescolar , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Resultado del Tratamiento

RESUMEN

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.

Asunto(s)

Arginina , Busulfano , Medicamentos Herbarios Chinos , Espermatogénesis , Testículo , Masculino , Animales , Busulfano/efectos adversos , Busulfano/toxicidad , Ratones , Testículo/efectos de los fármacos , Testículo/metabolismo , Espermatogénesis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Estrés Oxidativo/efectos de los fármacos , Reproducción/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo

RESUMEN

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.

Asunto(s)

Autofagia , Barrera Hematotesticular , Busulfano , Caprilatos , Estrés Oxidativo , Células de Sertoli , Espermatogénesis , Masculino , Animales , Barrera Hematotesticular/efectos de los fármacos , Barrera Hematotesticular/metabolismo , Busulfano/efectos adversos , Caprilatos/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratones , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Humanos , Espermatogénesis/efectos de los fármacos , Autofagia/efectos de los fármacos , Infertilidad Masculina/tratamiento farmacológico , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/patología , Testículo/efectos de los fármacos , Testículo/patología , Testículo/metabolismo , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Adulto

RESUMEN

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.

Asunto(s)

Busulfano , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Trasplante Homólogo , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/efectos adversos , Busulfano/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto , Persona de Mediana Edad , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/epidemiología , Estudios Retrospectivos , Adulto Joven , Adolescente , Resultado del Tratamiento , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos

RESUMEN

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.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedades del Sistema Nervioso , Humanos , Busulfano/efectos adversos , Estudios Retrospectivos , Antifúngicos/uso terapéutico , Equinocandinas/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre , Enfermedades del Sistema Nervioso/etiología , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Enfermedad Injerto contra Huésped/etiología

RESUMEN

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.

Asunto(s)

Busulfano , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina , Humanos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Busulfano/efectos adversos , Busulfano/administración & dosificación , Estudios Retrospectivos , Agonistas Mieloablativos/efectos adversos , Agonistas Mieloablativos/uso terapéutico , Agonistas Mieloablativos/administración & dosificación , Irradiación Corporal Total/efectos adversos , Adulto Joven , Estudios de Seguimiento , Médula Ósea/efectos de la radiación , Médula Ósea/efectos de los fármacos , Anciano , Adolescente

RESUMEN

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .

Asunto(s)

Agammaglobulinemia , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Humanos , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Adenosina Desaminasa/genética , Adenosina Desaminasa/uso terapéutico , Busulfano/efectos adversos , Terapia Genética , Retroviridae/genética

RESUMEN

The purine analog fludarabine (Flu) plays a central role in reduced-intensity conditioning and myeloablative reduced-toxicity conditioning regimens because of limited nonhematologic toxicities. Few reports assess the impact of different dose of Flu on the clinical outcomes and the Flu doses vary across reports. To compare the effect of Flu dose, the clinical outcomes of patients who received Flu and busulfan (FB; n = 1647) or melphalan (Flu with melphalan (FM); n = 1162) conditioning for unrelated bone marrow transplantation were retrospectively analyzed using Japanese nationwide registry data. In the FB group, high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were given to 1334 and 313 patients, respectively. The 3-year overall survival (OS) rates were significantly higher in the HFB group than in the LFB group (49.5% versus 39.2%, P < .001). In the HFB and LFB groups, the cumulative incidences were 30.4% and 36.6% (P = .058) for 3-year relapse and 25.1% and 28.1% (P = .24) for 3-year nonrelapse mortality (NRM), respectively. In the multivariate analysis for OS and relapse, Flu dose was identified as an independent prognostic factor (hazard ratio: 0.83, P = .03; hazard ratio: 0.80, P = .043). In the FM group, high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were given to 118 and 1044 patients, respectively. The OS, relapse, and NRM after 3 years did not differ significantly between the HFM and LFM groups (48.3% versus 48.8%, P = .92; 23.7% versus 27.2%, P = .55; 31.9% versus 30.8%, P = .67). These findings suggest that high-dose Flu was associated with favorable outcomes in the FB group but not in the FM group.

Asunto(s)

Trasplante de Médula Ósea , Busulfano , Melfalán , Acondicionamiento Pretrasplante , Vidarabina , Vidarabina/análogos & derivados , Humanos , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Melfalán/efectos adversos , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Busulfano/efectos adversos , Adolescente , Anciano , Adulto Joven , Niño , Japón/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Resultado del Tratamiento

RESUMEN

BACKGROUND: The ovarian environment of premature ovarian insufficiency (POI) patients exhibits immune dysregulation, which leads to excessive secretion of numerous proinflammatory cytokines that affect ovarian function. An abnormal level of macrophage polarization directly or indirectly inhibits the differentiation of ovarian granulosa cells and steroid hormone production, ultimately leading to POI. Resveratrol, as a health supplement, has been widely recognized for its safety. There is a substantial amount of evidence indicating that resveratrol and its analogs possess significant immune-regulatory functions. It has also been reported that resveratrol can effectively inhibit the progression of POI. However, the underlying immunological and molecular mechanisms through which resveratrol inhibits the progression of POI are still unclear. RESULTS: Our preliminary reports have shown that resveratrol-ßcd, the beta-cyclodextrin complex of resveratrol, significantly enhances the stability of resveratrol. Resveratrol-ßcd could regulate the dysfunctional immune status of macrophages and T cells in the tumor microenvironment. In this study, we treated busulfan and cyclophosphamide (B/C)-treated mice, which were used as a POI model, with resveratrol-ßcd. After resveratrol-ßcd treatment, the levels of IL-6 in the ovaries were significantly increased, and the progression of POI was suppressed. IL-6 activated granulosa cells (GCs) through soluble IL-6R (sIL-6R), promoting autophagy in GCs. Resveratrol-ßcd and IL-6 had a synergistic effect on enhancing autophagy in GCs and promoting E2 secretion. CONCLUSIONS: We partially elucidated the immune mechanism by which resveratrol inhibits the progression of POI and the autophagy-regulating function of GCs. This provides a theoretical basis for using resveratrol to prevent POI in future studies and clinical guidance.

Asunto(s)

Menopausia Prematura , Insuficiencia Ovárica Primaria , Resveratrol , Animales , Femenino , Ratones , Autofagia , Busulfano/efectos adversos , Ciclofosfamida/efectos adversos , Células de la Granulosa , Interleucina-6 , Insuficiencia Ovárica Primaria/terapia , Resveratrol/farmacología

RESUMEN

Patients undergoing hematopoietic stem cell transplantation (HSCT) for hematologic malignancies during childhood have an increased risk of developing long-term sequelae that are in part attributable to the conditioning regimen. The present study aimed to assess the occurrence of long-term toxicities in a population of children who underwent HSCT for hematologic malignancies using either treosulfan or busulfan in the conditioning regimen. The cumulative incidences of growth impairment, altered gonadal function, altered thyroid function, cataracts, secondary malignant neoplasia, and altered pulmonary function were evaluated retrospectively by univariable and multivariable analyses in a population of 521 pediatric patients with acute leukemias or myelodysplastic syndromes treated in 20 Italian transplant centers affiliated with the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP). The median duration of follow-up for the entire study population was 7.1 years (range, 1 to 16 years). Overall, a larger proportion of patients given busulfan developed long-term toxicities compared to patients treated with treosulfan (34% versus 20%; P = .01). In univariable analysis, gonadal toxicity developed in 10% of patients who received treosulfan (95% confidence interval [CI], 3% to 15%), compared with 38% (95% CI, 24% to 39%) of busulfan-treated patients (P = .02), and this finding was confirmed by multivariable analysis (relative risk, .51; 95% CI, .34 to .76; P = .0009). We did not find any statistically significant associations between the occurrence of other long-term toxicities and the use of either busulfan or treosulfan. This study provides evidence that the use of treosulfan is correlated with a reduced incidence of gonadal toxicity in children undergoing HSCT for hematologic malignancies.

Asunto(s)

Busulfano/análogos & derivados , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Niño , Busulfano/efectos adversos , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia

RESUMEN

A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk ß-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with ß-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Talasemia beta , Humanos , Talasemia beta/terapia , Busulfano/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Tiotepa , Acondicionamiento Pretrasplante/métodos , Enfermedad Injerto contra Huésped/inducido químicamente , Enfermedad Injerto contra Huésped/tratamiento farmacológico

RESUMEN

Here we describe two patients that required interruption of a busulfan (BU) containing conditioning regimen due to severe mental disorder before stem cell transplantation. The first patient was a 66-year-old man scheduled for unrelated peripheral blood stem cell transplantation with fludarabine/BU conditioning for myelodysplastic syndrome. He received 9.6 mg/kg BU and developed hallucinations that worsened the next day. BU was stopped on the final day, but the patient became comatose (grade 4). He recovered the next day. The second patient was a 69-year-old man scheduled for autologous peripheral blood stem cell transplantation with thiotepa (TT)/BU conditioning for cerebral nervous system relapse of mantle cell lymphoma. He received 12.8 mg/kg BU and developed hallucinations. His mental symptoms worsened on the next day, and thus administration was stopped on the second day of TT. His symptoms improved the next day. Both patients were over 65 years old, and their psychiatric symptoms worsened 1-2 days after the final dose of BU. Our findings suggest that BU may cause psychiatric disorders in elderly patients. When performing BU conditioning, it may be necessary to avoid azole antifungal medication and acetaminophen and to reduce the dose or perform therapeutic dose monitoring for elderly patients.

Asunto(s)

Busulfano , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Anciano , Humanos , Masculino , Busulfano/efectos adversos , Ciclofosfamida , Alucinaciones/inducido químicamente , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Recurrencia Local de Neoplasia , Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante/efectos adversos , Vidarabina

RESUMEN

OBJECTIVES: Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with transfusion-dependent thalassemia major. In recent years, a number of novel approaches have improved patient outcomes and quality of life by minimizing the toxicity of conditioning regimens. The objective of this study was to compare the role of treosulfan- and busulfan-based conditioning in transfusion-dependent thalassemia. MATERIALS AND METHODS: Data were collected retrospectively on 121 children with beta thalassemia major who underwent hematopoietic stem cell transplant using treosulfan-based (n = 37) or busulfan-based (n = 84) conditioning regimens between 2012 and 2022. RESULTS: Two-year overall survival was 87.5% in the busulfan-based conditioning group and 91.1% in the treosulfan-based conditioning group.The group given the busulfan regimen compared with treosulfan regimen had significantly increased number of side effects (58.3% vs 21.6%, respectively; P < .001). When the busulfan-based regimen by level was evaluated, we observed no significant differences between the frequency of side effects according to drug serum levels. In addition, no significant differences were shown between the 2 regimen groups for cumulative incidence of acute and chronic graft-versus-host disease. CONCLUSIONS: The safety and effectiveness of a treosulfan-based myeloablative conditioning regimen has been confirmed by ourretrospective investigation of pediatric patients with beta thalassemia.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Talasemia beta , Humanos , Niño , Busulfano/efectos adversos , Talasemia beta/diagnóstico , Talasemia beta/terapia , Talasemia beta/complicaciones , Estudios Retrospectivos , Calidad de Vida , Turquía , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Vidarabina

RESUMEN

Introduction: Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. Methods: Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. Results: Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). Conclusions: a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Hipogonadismo , Adulto , Niño , Humanos , Masculino , Busulfano/efectos adversos , Células Intersticiales del Testículo , Estudios Retrospectivos , Hipogonadismo/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Testosterona

RESUMEN

Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the role of BBR on POI is still unknown. In this study, we investigated the role of BBR on ovarian function decline by establishing a POI mouse model using cyclophosphamide (CTX) and busulfan (BU). Our results showed that POI was attenuated by BBR, which was evidenced by enhanced body weight and ovarian weight, improved morphology of ovary, increased the number of healthy follicles, decreased the production of atretic follicles and restored serum hormone levels, including estradiol, anti-Müllerian hormone and follicle-stimulating hormone. In addition, we showed that germ cell function markers, mouse vasa homologue (MVH) and octamer-binding transcription factor 4 (OCT4) were enhanced by BBR, at both protein and mRNA levels. Furthermore, our results revealed that BBR inhibited inflammation and oxidative stress by reducing nuclear factor kappa B (NF-κB) and enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Taken together, we demonstrate that BBR can effectively improve ovarian function in POI mice, which is mainly mediated by reducing oxidative stress and inflammatory response. Our study also provides new strategy for POI treatment.

Asunto(s)

Berberina , Insuficiencia Ovárica Primaria , Ratones , Femenino , Humanos , Animales , Busulfano/efectos adversos , Berberina/farmacología , Berberina/uso terapéutico , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/prevención & control , Insuficiencia Ovárica Primaria/metabolismo , Ciclofosfamida/toxicidad , Estradiol

RESUMEN

PURPOSE: This study aimed to establish an optimal model to predict the busulfan (BU) area under the curve at steady state (AUCss) by using machine learning (ML). PATIENTS AND METHODS: Seventy-nine adult patients (age ≥18 years) who received BU intravenously and underwent therapeutic drug monitoring from 2013 to 2021 at Fujian Medical University Union Hospital were enrolled in this retrospective study. The whole dataset was divided into a training group and test group at the ratio of 8:2. BU AUCss were considered as the target variable. Nine different ML algorithms and one population pharmacokinetic (pop PK) model were developed and validated, and their predictive performance was compared. RESULTS: All ML models were superior to the pop PK model (R2 = 0.751, MSE = 0.722, 14 and RMSE = 0.830) in model fitting and had better predictive accuracy. The ML model of BU AUCss established through support vector regression (SVR) and gradient boosted regression trees (GBRT) had the best predictive ability (R2 = 0.953 and 0.953, MSE = 0.323 and 0.326, and RMSE = 0.423 and 0.425). CONCLUSION: All the ML models can potentially be used to estimate BU AUCss with the aim of facilitating rational use of BU on the individualized level, especially models built by SVR and GBRT algorithms.

Asunto(s)

Busulfano , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Adolescente , Busulfano/efectos adversos , Busulfano/farmacocinética , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/métodos , Monitoreo de Drogas/métodos , Área Bajo la Curva

RESUMEN

Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS.

Asunto(s)

Busulfano , Trasplante de Células Madre Hematopoyéticas , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Busulfano/efectos adversos , Estudios Retrospectivos , Trasplante Homólogo , Acondicionamiento Pretrasplante/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos

RESUMEN

OBJECTIVES: It is unclear whether patients with oral foci of infection should be approved for hematopoietic stem cell transplant with or without posttransplant cyclophosphamide. We compared the presence of oral foci of infection status on the effects of various conditioning regimens for such patients. MATERIALS AND METHODS: Three groups were classified as autologous (carmustine-etoposide-cytarabinemelphalan, mitoxantrone-melphalan, and melphalan 200 mg/m² groups; n = 502 patients), and 6 groups were classified as allogeneic (busulfan-fludarabinerabbit anti-T-lymphocyte globulin, busulfanfludarabine-posttransplant cyclophosphamide, fludarabine-cyclophosphamide-anti-T-lymphocyte globulin, busulfan-fludarabine-anti-T-lymphocyte globulin-posttransplant cyclophosphamide, total body irradiation-posttransplant cyclophosphamide, and other; n = 428 patients). Data were collected from a database that met international accreditation requirements. We evaluated dental radiological findings and calculated interobserver reliability. RESULTS: Oral foci of infections increased febrile neutropenia and bacterial infection frequencies in both groups but only increased mucositis frequency in patients with allogeneic treatment. The frequencies of oral foci of infection-related complications were similar in both the autologous and allogeneic groups. Rate of graft-versus-host disease was not affected by oral foci of infection status. Periodontitis/cysts and periapical lesions increased the risk of infections at day 100 in the mitoxantrone-melphalan group versus the melphalan 200 mg/m² group. We observed no differences among the autologous transplant groups in terms of early mortality. Similarly, no differences in early mortality were observed among the allogeneic groups. CONCLUSIONS: Transplant is a valid option in patients with oral foci of infections undergoing various autologous and allogeneic transplant protocols when time is of the essence, even at myeloablative dose intensities.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Busulfano/efectos adversos , Melfalán/uso terapéutico , Mitoxantrona , Reproducibilidad de los Resultados , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre/efectos adversos , Ciclofosfamida , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico

RESUMEN

Introduction: Premature ovarian failure (POF) is a major cause of infertility among women of reproductive age. Unfortunately, there is no effective treatment available currently. Researchers have shown that immune disorders play a significant role in the development of POF. Moreover, growing evidence suggest that Chitosan Oligosaccharides (COS), which act as critical immunomodulators, may have a key role in preventing and treating a range of immune related reproductive diseases. Methods: KM mice (6-8 weeks) received a single intraperitoneal injection of cyclophosphamide (CY, 120mg/kg) and busulfan (BUS, 30mg/kg) to establish POF model. After completing the COS pre-treatment or post-treatment procedures, peritoneal resident macrophages (PRMs) were collected for neutral erythrophagocytosis assay to detect phagocytic activity. The thymus, spleen and ovary tissues were collected and weighed to calculate the organ indexes. Hematoxylin-eosin (HE) staining was performed to observe the histopathologic structure of those organs. The serum levels of estrogen (E2) and progesterone (P) were measured via the enzyme-linked immunosorbent assay (ELISA). The expression levels of immune factors including interleukin 2 (IL-2), interleukin 4 (IL-4), and tumor necrosis factor α (TNF-α), as well as germ cell markers Mouse Vasa Homologue (MVH) and Fragilis in ovarian tissue, were analyzed by Western blotting and qRT-PCR. In addition, ovarian cell senescence via p53/p21/p16 signaling was also detected. Results: The phagocytic function of PRMs and the structural integrity of thymus and spleen were preserved by COS treatment. The levels of certain immune factors in the ovaries of CY/BUS- induced POF mice were found to be altered, manifested as IL-2 and TNF-α experiencing a significant decline, and IL-4 presenting a notable increase. Both pre-treatment and post-treatment with COS were shown to be protective effects against the damage to ovarian structure caused by CY/BUS. Senescence-associated ß-galactosidase (SA-ß-Gal) staining results showed that COS prevents CY/BUS-induced ovarian cell senescence. Additionally, COS regulated estrogen and progesterone levels, enhanced follicular development, and blocked ovarian cellular p53/p21/p16 signaling which participating in cell senescence. Conclusion: COS is a potent preventative and therapeutic medicine for premature ovarian failure by enhancing both the ovarian local and systemic immune response as well as inhibiting germ cell senescence.

Asunto(s)

Quitosano , Insuficiencia Ovárica Primaria , Ratones , Humanos , Femenino , Animales , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Insuficiencia Ovárica Primaria/patología , Busulfano/efectos adversos , Interleucina-2/uso terapéutico , Quitosano/farmacología , Interleucina-4 , Factor de Necrosis Tumoral alfa/uso terapéutico , Progesterona , Proteína p53 Supresora de Tumor , Ciclofosfamida/uso terapéutico , Reproducción , Estrógenos/efectos adversos , Oligosacáridos/uso terapéutico

RESUMEN

With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC] <70 mg*h/L) was not associated with a reduced risk of gonadal dysfunction (odds ratio [OR], .92; 95% confidence interval [CI], .25 to 3.49; P = .90). In the Treo cohort, 32 patients were evaluable and gonadal insufficiency occurred in 9 patients (28%). Lower Treo exposure (AUC <1750 mg*h/L on day 1) was not associated with a reduced risk of gonadal dysfunction (OR, 1.6; 95% CI, .16 to 36.6; P = .71). Our data do not support the premise that reduced-intensity Bu-based conditioning reduces the risk for gonadal toxicity, and it is unlikely that therapeutic drug monitoring-based reduced treosulfan exposure will further limit the risk of gonadal dysfunction.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Lesiones Precancerosas , Humanos , Niño , Adolescente , Busulfano/efectos adversos , Estudios Retrospectivos , Calidad de Vida , Acondicionamiento Pretrasplante/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Lesiones Precancerosas/tratamiento farmacológico