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1.
Leuk Res ; 110: 106689, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34592699

RESUMO

INTRODUCTION: Hodgkin's (HL) and non-Hodgkin's (NHL) lymphomas have usually high cure rates. The standard of care for chemosensitive relapsed/refractory lymphoma patients is salvage chemotherapy followed by AHSCT. Due to carmustine and melphalan shortages, alternative pre-AHSCT conditioning regimens with similar tolerance and response were needed. OBJECTIVES: To compare the efficacy and toxicity profile between relapsed/refractory HL and NHL lymphomas given BEAM or BuCyE. METHODS: A retrospective analyses of 122 patients in a Brazilian center was made. OS and PFS were calculated by Kaplan-Meier and compared by log rank. Toxicity and engraftment data were also compared. RESULTS: Most clinical characteristics were similar between groups, although a higher frequency of grade ≥ 2 mucositis (p = .01) was seen in the BuCyE group. No significant difference in OS or PFS were observed between the groups. CONCLUSION: BEAM and BuCyE are well tolerated with similar toxicity profiles and survival outcomes. Therefore, BuCyE conditioning regimen can be considered an alternative to BEAM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença de Hodgkin/terapia , Linfoma não Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Bussulfano/administração & dosagem , Carmustina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Doença de Hodgkin/patologia , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Transplante Autólogo , Adulto Jovem
2.
Reprod Health ; 18(1): 189, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556135

RESUMO

BACKGROUND: Spermatogonial stem cells (SSCs) in the testis are crucial for transferring genetic information to the next generation. Successful transplantation of SSCs to infertile men is an advanced therapeutic application in reproductive biology research. METHODS: In this experimental research, both in vitro and in vivo characterization of undifferentiated and differentiated SSCs were performed by morphology-immunocytochemistry (ICC), immunohistochemistry (IMH), Fluidigm Real-Time polymerase chain reaction (RT-PCR) and flow cytometry analysis. The isolated SSCs were finally microinjected into the rete testis of busulfan-treated mice. The compact undifferentiated and more loosely connected round differentiated SSCs were isolated during testicular cell expansion from their specific feeder layer. RESULTS: ICC analysis indicated high and low expression levels of Zbtb16 in undifferentiated and differentiated germ cells. Also, IMH analysis showed different expression levels of Zbtb16 in the two different germ stem cell populations of the testicular tissue. While Fluidigm RT-PCR analysis indicated overexpression of the TAF4B germ cell gene, the expression of DAZL, VASA, and Zbtb16 were down-regulated during the differentiation of SSCs (P < 0.05). Also, flow cytometry analysis confirmed the significant downregulation of Itgb1 and Itga4 during differentiation. By transplantation of SSCs into busulfan-treated NOD/SCID mice, GFP-labeled sperm cells developed. CONCLUSIONS: In the current study, we performed a transplantation technique that could be useful for the future microinjection of SSCs during infertility treatment and for studying in vivo differentiation of SSCs into sperm.


Assuntos
Bussulfano , Espermatogônias , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Túbulos Seminíferos , Espermatogênese , Células-Tronco
3.
Cells ; 10(9)2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34572051

RESUMO

Spermatogenesis is a process within the testis that leads to the production of spermatozoa. It is based on a population of spermatogonial stem cells, which have the capacity to self-renew and to differentiate throughout life to ensure the functions of reproduction are maintained. Male fertility disorders are responsible for half of the cases of infertility in couples worldwide. It is well known that cancer treatments are associated with reversible or irreversible fertility disorders. Busulfan (Bu) is an alkylating agent that significantly inhibits spermatogenesis. The present study relied on a combination of in vivo and in vitro approaches as well as RNAseq analysis to characterize the effects of Bu, in which mouse testes were used as a model. An in silico analysis revealed that many of the Bu-modulated genes are potentially regulated by the SIN3 Transcription Regulator Family Member A (SIN3A) and E2F Transcription Factor (E2F) families of transcription factors. The results demonstrate that the deregulated genes function in processes related to the cell cycle, DNA repair, and cell death mechanisms, including the Tumor Protein 53 (TP53) pathway. This reinforces the role of the TP53 signaling pathway as a major player in Bu effects. In addition, Bu altered the patterns of mRNA accumulation for various genes in undifferentiated spermatogonia. This work provides significant insight into the kinetics and impacts of busulfan, which could pave the way for developing strategies to minimize the impact of chemodrugs and, thus, could lead to germ cell lineage regeneration following anticancer treatments.


Assuntos
Bussulfano/farmacologia , Fertilidade/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/farmacologia , Testículo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA-Seq , Testículo/metabolismo
4.
Int J Cancer ; 149(12): 2075-2082, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34398971

RESUMO

Previous studies highlight the need for a more active conditioning therapy in high-risk or refractory and relapsed lymphomas. Our preclinical research shows that histone deacetylase inhibitors, such as either vorinostat or chidamide, sensitize lymphoma cells to the cytotoxic combination of cladribine, gemcitabine and busulfan, leading to cell apoptosis. To evaluate the efficacy of this chidamide-cladribine-gemcitabine-busulfan (ChiCGB) combination as a new conditioning therapy, we conducted a Phase II trial, as described here. Patients with high-risk, relapsed/refractory lymphomas received ChiCGB as conditioning therapy, after transplantation with autologous peripheral stem cells. The sample comprised 105 patients in total: 60 with B-cell non-Hodgkin lymphomas (B-NHL) and 45 with T-cell or natural killer/T-cell lymphoma (NK/T). All patients eventually achieved full hematopoietic recovery. Neutrophils and platelets were engrafted at a median of 10 days (8-14) and 13 days (8-38), respectively. There was no transplant-related mortality within 100 days of transplant. Neutropenic fever, mucositis and atopic dermatitis were the observed nonhematologic toxicities. At a median follow-up of 35.4 months, 80.6% of the patients presented with no tumor progression, and the overall survival (OS) reached as high as 86.1%. Concerning the OS rate, 94.5% of patients with B-NHL and 75.4% of patients with T-cell or NK/T lymphomas survived. These findings demonstrate the safety and validity of the proposed combined therapy for high-risk and refractory/relapsed lymphomas. Our study was registered on the Clinical Trial Registry (clinicaltrials.gov, NCT03151876).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Cladribina/administração & dosagem , Cladribina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Intervalo Livre de Progressão , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Adulto Jovem
5.
Bull Cancer ; 108(9): 877-885, 2021 Sep.
Artigo em Francês | MEDLINE | ID: mdl-34246455

RESUMO

BACKGROUND: Hematopoietic stem cell allograft is a treatment for patients with severe constitutional or acquired hematopoietic system diseases. This act is always linked to complications requiring multidisciplinary care. Our study describes the post-allograft cutaneous complications. METHODS: A prospective study was conducted at the Hematology department of "20 Août Hospital" in Casablanca during a period going from January 2018 to December 2020; including all patients who presented acute or chronic cutaneous complications post-allograft. RESULTS: Twenty-five patients were included. All patients received induction chemotherapy (Busulfan/Fludarabine or Busulfan/Melphalan). A skin infection was found in 8 patients : four cases of Malassezia folliculitis, one case of perineal zona, one case of genital herpes, one case of varicella and one case of Candida sepsis. The acute graft versus host reaction was found in 3 patients, revealed by an erythematous rash all over the body. The chronic graft versus host reaction was found in five patients on a lichenoid form. Nine patients had a hyperpigmentation of the folds followed by detachment in the same areas, concluding to a Busulfan toxidermy. DISCUSSION: Hematopoietic stem cell allograft has many complications. The literature mainly specifies hematological and digestive complications, while skin complications are little described. Our series is special by reporting different types and mechanisms of skin complications that can occur; with a predominance of skin graft-on-host reactions and infections. It also reports an unusual Busulfan toxidermy.


Assuntos
Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Dermatopatias/etiologia , Doença Aguda , Adolescente , Adulto , Aloenxertos , Bussulfano/uso terapêutico , Candidíase/diagnóstico , Varicela/diagnóstico , Criança , Doença Crônica , Dermatomicoses/diagnóstico , Dermatomicoses/microbiologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Herpes Genital/diagnóstico , Humanos , Quimioterapia de Indução/métodos , Malassezia , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Marrocos , Estudos Prospectivos , Dermatopatias/patologia , Dermatopatias Infecciosas/diagnóstico , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto Jovem
6.
J Pharm Biomed Anal ; 203: 114216, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34182411

RESUMO

A fast and reliable method based on two-channel liquid chromatography coupled to tandem mass spectrometry was developed and successfully validated for quantification of busulfan. The drug vehicle polyethylene glycol 400 was quantified simultaneously in patient samples. The sample preparation consisted of simple protein precipitation using a mixture of methanol and zinc sulphate containing busulfan-d8 as internal standard. Chromatographic separation was performed on a short biphenyl column (30 mm × 3.0 mm, 5 µm particles) using a step gradient from 30 % to 85 % methanol, ensuring co-elution of the analyte and internal standard. Quantification was performed using the mass transition of 264.1 > 151.1 for busulfan and 272.1 > 159.1 for the internal standard. Using only 20 µL of plasma sample, the lower limit of quantification was 25 ng/mL. Signal to noise ratio at the lower limit of quantification exceeded 300. The assay performance was not adversely affected by matrix effects originating from drug formulation excipients or other sample components. The coefficient of variation was ≤4 % and the mean accuracy 101-108 % across the calibration range 25-5 000 ng/mL. Chromatographic run time was 2 min and 8 s, allowing an effective run-time of 1 min and 10 s when using two alternating LC-channels. The assay has been implemented in routine practice with accreditation according to the ISO 15189 standard, and performs well in external quality control assessments. We present for the first time that shortly after an IV infusion of busulfan, the plasma levels of polyethylene glycol 400 may be in the range of 400-800 mg/L. The presence of these levels of detergent in patient samples may have detrimental effects on assay performance in LC-MS/MS, not limited to busulfan assays. This may be a concern for any LC-MS/MS analysis performed on samples collected within the first 24 h after an IV infusion of busulfan.


Assuntos
Bussulfano , Excipientes , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Composição de Medicamentos , Humanos , Plasma , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(5): 449-457, 2021 May 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34148880

RESUMO

OBJECTIVES: To establish mouse bone marrow transplantation by pretreatment with chemotherapy, and to explore the dynamic changes of immune cells in the early stage of allogeneic transplantation in the spleen of mice. METHODS: Mice were divided into 4 groups (80 mg/kg group, 100 mg/kg group, 120 mg/kg group, and 150 mg/kg group) according to the difference in dose of busulfan. The mice were treated with busulfan and cyclophosphamide combined chemotherapy, and the appropriate dosage was determined by evaluating the myeloablative effect and drug toxicity. According to the type of the genetic transplantation, the mice were also divided into 4 groups: An allogeneic transplantation group, a homogenic transplantation group, a chemotherapy alone group, and a normal control group. The mice were pretreated with busulfan and cyclophosphamide before bone marrow transplantation. In the allogeneic transplantation group, the suspension of splenocytes was prepared at the first day, the 3rd day, the 5th day, and the 8th day after transplantation for flow cytometry detection, and the dynamic changes of splenic immune cells were analyzed. The homogeneic transplantation group served as the concurrent control, the normal control group served as the control of basic value of spleen immune cells, and the chemotherapy alone group was used to evaluate the myeloablative effect. RESULTS: 1) The optimal dose of busulfan was 100 mg/kg. The combination of busulfan and cyclophosphamide can restore the hematopoiesis of transplanted mice, and the toxicity associated with pretreatment is small. 2) In the allogeneic transplantation group: The hematopoietic reconstitution and high donor chimerism rate were achieved after transplantation. In the early phase of bone marrow transplantation, the T lymphocytes were the main cell group, while the recovery of B lymphocytes was relatively delayed. The dendritic cells and natural killer cells from donors were the earliest cells to recover and achieve high chimerism rate compared with T cells and B cells. Most T cells were in the initial T cell state within 5 days after allogeneic transplantation. However, in the 5th day after transplantation, these cells were mainly in the effective memory phenotype. The reconstruction of donor-derived naive T cells was slow, but the reconstruction of donor-derived effective memory T cells and regulatory T cells was relatively fast. 3) In the homogeneic transplantation group: The mice could recover hematopoiesis and the recovery of B lymphocytes was delayed. 4) In the chemotherapy alone group: All mice died in 12-15 days after chemotherapy, and the peripheral blood routine showed pancytopenia before death. CONCLUSIONS: Pretreatment with chemotherapy can successfully establish the mouse model of bone marrow transplantation. There are difference in the proportion of T cells, B cells, natural killer cells, dendritic cells, effector memory T cells, initial T cells, and regulatory T cells after transplantation, and the relationship between donor and recipient is also changed.


Assuntos
Transplante de Medula Óssea , Bussulfano , Animais , Células da Medula Óssea , Proliferação de Células , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Transplante Homólogo
8.
Andrologia ; 53(8): e14144, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34143903

RESUMO

This study aimed at the efficacy of sequential treatment of bone marrow-derived mesenchymal stem cell secretion for busulfan-treated azoospermia in mice. The conditioned media (CM) was obtained from bone marrow mesenchymal stem cells (MSCs) or 293 cells. Chemically induced azoospermia mice received 200 µl MSC-CM or 293-CM twice a week intravenously for three consecutive weeks. The histological assessment of spermatogenic recovery quantifying the expression of meiosis-associated genes, and Sertoli cell barrier functional factors were assessed. The characteristics of TM4 cells (Sertoli cell line) after pre-incubation of MSC-CM in vitro were also obtained. The MSC-CM group had the most spermatogenic colonies among the three groups (p < .05), but no spermatids were seen. Expressions of the meiosis-associated genes Dazl, Vasa, Miwi, Stra8, CyclinA1, Pgk2 and Scp3 in MSC-CM testis were remarkably higher compared with 293-CM and busulfan groups respectively (p < .05). The levels of Sertoli cell barrier functional factors, for example ICAM-1 and N-cadherin, were significantly increased during MSC-CM treatment (p < .05). Moreover, pre-incubation of MSC-CM particularly accelerated the CD54 (ICAM-1) and CD44 expressions of TM4 cells and promoted cell inherent adhesion. MSC-CM treatment can significantly improve the short-term restoration of spermatogonial structures of chemically induced azoospermia related to facilitating Sertoli cell adhesion integrity.


Assuntos
Azoospermia , Células-Tronco Mesenquimais , Animais , Azoospermia/induzido quimicamente , Azoospermia/terapia , Bussulfano/toxicidade , Humanos , Masculino , Camundongos , Células de Sertoli , Espermatogênese
10.
Cells ; 10(5)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946560

RESUMO

In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient's diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.


Assuntos
Bussulfano/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Agonistas Mieloablativos/farmacologia , Condicionamento Pré-Transplante/métodos , Animais , Benzilaminas/farmacologia , Células Cultivadas , Ciclamos/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Reconstituição Imune , Camundongos , Camundongos Endogâmicos BALB C
11.
Asian Pac J Cancer Prev ; 22(5): 1639-1644, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048196

RESUMO

BACKGROUND: The side effects of conditioning regimens on the success rate of allogeneic transplantation around the world have been challenging. In this study, we aimed to investigate the side effect of Bu/Cy and Bu/Flu regimens on our patients who underwent allogeneic bone marrow transplantation. METHODS: We analyzed 180 patients receiving bone marrow transplantation in Taleghani Hospital, in Tehran, Iran between April 2016 and December 2019. Patients in group A received a combination of intravenous busulfan 0.8 mg/kg QID over two hours for 4 consecutive days (12.8 mg/kg in total)(Savani et al., 2006) and cyclophosphamide 60 mg/kg per day for two consecutive days. Patients in group B received busulfan the same as the first group in combination with fludarabine equal to 40 mg/m² per day. Patients were followed up at regular intervals up to two years after transplantation. RESULT: Various items were evaluated for patients, including cardiopulmonary function, psychological disorders, GVHD, and endocrine disorders such as hypothyroidism, fertility, or gonad dysfunction.  Primary hypothyroidism developed in 13.3% and 11.1% of the Bu/Cy and Bu/Flu groups, respectively (p=0.230). None of the patients in either group experienced infertility or gonad dysfunction. In group A versus group B, pulmonary diseases were detected in  4.4% versus 6.6% of BMT recipients, respectively (p = 0.223). In both groups, mitral and tricuspid regurgitation were observed in patients (8.9% vs. 11.1%; p = 0.189). Incidence of Psychological disorders was no significant difference between the two groups. 32.2% of group A versus 34.45%  of group B had skin and liver GVHD, respectively (p = 0.235). CONCLUSION: The therapeutic-related adverse effects of the two conditioning regimens in patients who underwent allogeneic bone marrow transplant were almost similar. To improve quality of life and overall survival among BMT patients, careful evaluation of treatment-related complications should be part of the regular follow-up of them.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Idoso , Bussulfano/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/radioterapia , Feminino , Seguimentos , Neoplasias Hematológicas/patologia , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto Jovem
12.
Ann Hematol ; 100(9): 2363-2373, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33988738

RESUMO

With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6-8/8 HLA-matched unrelated donor (MUD) or 6-7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6-7/8 MRD, and 42 (36.5%) from a 6-7/8 MUD. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was higher in the 6-7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6-7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6-7/8 MUD, 6-7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6-7/8 MRD or 6-7/8 MUD is comparable to that from an 8/8 MUD.


Assuntos
Anemia Aplástica/terapia , Bussulfano/uso terapêutico , Antígenos HLA/análise , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Histocompatibilidade , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
13.
J Med Invest ; 68(1.2): 196-201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994471

RESUMO

The prognosis of relapsed or refractory lymphoma with central nervous system (CNS) involvement remains poor because of the lack of anticancer drugs with sufficient CNS penetration. [Case 1] A 65-year-old man was diagnosed with Stage IV mantle cell lymphoma. After two courses of chemotherapy and autologous hematopoietic stem cell (HSC) collection, urinary retention with fever developed. Cerebrospinal fluid analysis revealed leptomeningeal involvement, which was refractory to high-dose methotrexate therapy. Autologous peripheral blood stem cell transplantation (ASCT) was performed, followed by intravenous busulfan (ivBU), cyclophosphamide, and etoposide ; thereafter, no relapse has been detected for over six years. [Case 2] A 40-year-old woman with right lower hemiplegia was diagnosed with primary CNS lymphoma. Although four courses of high-dose methotrexate therapy were administered, the cerebral tumor increased in size. HSCs were collected after methotrexate therapy, and ASCT was performed in addition to conditioning using ivBU, cyclophosphamide, and etoposide, followed by whole-brain and local boost irradiation. She achieved complete remission, but relapsed two years after ASCT. High-dose ivBU-containing conditioning regimens with ASCT may be useful for refractory B-cell lymphoma with CNS involvement. J. Med. Invest. 68 : 196-201, February, 2021.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano , Sistema Nervoso Central , Terapia Combinada , Feminino , Humanos , Linfoma de Células B/terapia , Masculino , Recidiva Local de Neoplasia , Tiotepa , Transplante Autólogo
14.
Cancer Chemother Pharmacol ; 88(3): 379-391, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34021809

RESUMO

AIM: To assess the ability of model-based personalised dosing tools to estimate busulfan exposure (i) in comparison to clinically used intensive sampling exposure estimation procedure, (ii) using limited sampling strategies and (iii) to predict changes in busulfan clearance during busulfan treatment. METHODS: Data on intravenous busulfan dosing for patients with 4 consecutive days were entered into Bayesian forecasting software, InsightRX and NextDose. Prediction of busulfan cumulative exposure was compared to current clinical practice estimation, aiming for pre-defined individualised target of cumulative exposure. Estimation performance was tested given several limited sampling strategies. RESULTS: Thirty-two paediatric patients (0.2-16.5 years) provided a total of 103 daily exposure measurements estimated using 7 samples taken per day (full sampling), with 19 patients having sampling following all doses administered. Both software tools utilising Bayesian methods provided acceptable relative bias and precision of cumulative exposure estimations under the tested sampling scenarios. Relative bias ranged from median RE of 0.1-14.6% using InsightRX and from 3.4-7.8% using NextDose. Precision ranged from median RMSE of 0.19-0.32 mg·h·L-1 for InsightRX and 0.08-0.1 mg·h·L-1 for NextDose. A median reduction in busulfan clearance from day 1 to day 4 was observed in the clinical data (-10.9%), when using InsightRX (-18.6%) and with NextDose (-14.7%). CONCLUSION: Bayesian methods were shown to have relatively low bias and precisely estimate busulfan exposure using intensive sampling and several limited sampling strategies, which provides evidence for prospective studies to evaluate these tools in clinical practice. A trend to overestimation of exposure using Bayesian methods was observed compared to clinical practice. Reduction of busulfan clearance from day 1 to 4 of once daily dosing was confirmed and should be considered when adjusting doses.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Modelos Biológicos , Administração Intravenosa , Adolescente , Antineoplásicos Alquilantes/farmacocinética , Teorema de Bayes , Bussulfano/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Software
15.
Transplant Cell Ther ; 27(6): 490.e1-490.e8, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823167

RESUMO

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM × minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM × min (range, 3462 to 5189 µM × minute) for patients with SOS and 3512 µM × min (2360 to 5455 µM × minute) (P = .0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Neuroblastoma , Bussulfano/efeitos adversos , Criança , Humanos , Quimioterapia de Indução , Melfalan/efeitos adversos , Neuroblastoma/tratamento farmacológico , Transplante Autólogo
16.
Transplant Cell Ther ; 27(7): 601.e1-601.e7, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33845259

RESUMO

The prognosis of acute leukemia refractory to induction chemotherapy or immunotherapy is dismal. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is widely used option for these patients, but only 10% to 15% of patients are cured by the procedure. Preclinical studies indicate that substitution of post-transplantation cyclophosphamide with bendamustine (PTB) in a prophylaxis regimen may be associated with an augmented graft-versus-leukemia (GVL) reaction. The aim of this study was to establish the optimal dose of PTB and evaluate the antileukemic effect of HSCT with this type of graft-versus-host disease (GVHD) prophylaxis. In the prospective trial (NCT02799147), PTB was administered in doses of 140, 100, and 70 mg/m2 on days +3 and +4. Myeloablative conditioning with fludarabine and oral busulfan was provided to all patients. The first 12 patients received single-agent PTB, and subsequent patients received combination therapy with tacrolimus and mycophenolate mofetil (MMF). Inclusion criteria were acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and ≥5% clonal blasts in the bone marrow. The study cohort comprised 22 patients with AML and 5 with ALL. Seven patients were enrolled in the 140 mg/m2 group (due to a stopping rule), and 10 each were enrolled in the 100 mg/m2 and 70 mg/m2 groups. Primary refractory disease was documented in 41% of the patients, and secondary refractory was documented in 59%. The median blast count in the bone marrow at the start of the conditioning was 18% (range, 6% to 97%). Transplantation was performed with a matched sibling donor in 5 patients, a matched or mismatched unrelated donor in 15, and a haploidentical donor in 7. Engraftment was documented in 93% of the patients, including 89% with complete remission and 63% without measurable residual disease. After PTB prophylaxis, we observed an unusual complication, a cytokine release syndrome (CRS), in 70% of the patients, including grade 3 to 5 CRS in 44%. The most frequent clinical symptoms included high fever in 67% of patients, abnormal liver function tests in 67%, pancreatitis in 63%, skin vasculitis in 56%, enterocolitis in 48%, inflammation of oral mucosa in 37%, disseminated intravascular coagulation in 37%, and central nervous system toxicity in 26%. The development of CRS was associated with use of an HLA-mismatched donor (75% versus 20%; P = .0043). Classic acute GVHD was documented in 44% of the patients. Grade II-IV acute GVHD was associated with grade 3 to 5 CRS (67% versus 25%; P = .031). Moderate and severe chronic GVHD in the 100-day survivors were more often observed after single-agent PTB than after the combination immunosuppression (100% versus 18%; P = .002). A relatively low relapse rate was observed for this patient population. Three-year overall survival was 28% (95% confidence interval [CI], 13% to 46%), and event-free survival was 29% (95% CI, 13% to 46%). Nonrelapse mortality was 46% (95% CI, 25% to 64%), and the cumulative incidence of relapse was 26% (95% CI, 11% to 44%). No relapses were documented after day +100. There were no statistically significant differences among the dose groups (P = .3481); however, survival was higher in the 100 mg/kg group. Survival was higher in patients with AML compared with those with ALL (35% versus 0%; P = .0157). PTB represents a promising option to augment the GVL effect in refractory AML; however, the high CRS-associated mortality necessitates additional studies to reduce the risk of this complication. Thus, routine clinical application of PTB cannot be currently recommended. Combination immunosuppression with tacrolimus and MMF partially ameliorates these complications, at least in the setting of HLA-matched allografts. Biological mechanisms of CRS and GVL after PTB require further elucidation.


Assuntos
Doença Enxerto-Hospedeiro , Cloridrato de Bendamustina/efeitos adversos , Bussulfano , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Estudos Prospectivos , Condicionamento Pré-Transplante
17.
Bone Marrow Transplant ; 56(8): 2005-2012, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33846563

RESUMO

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Bussulfano , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo
18.
Bone Marrow Transplant ; 56(8): 1964-1970, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33824442

RESUMO

Patients with poor risk acute myeloid leukemia (AML) have a dismal outcome. We hypothesized that combining decitabine with a standard non-myeloablative (NMA) conditioning regimen prior to allogeneic hematopoietic cell transplantation (allo HCT), might decrease the relapse incidence. We conducted a multicenter prospective phase II study (NCT02252107) with 10-day decitabine (20 mg/m2/day) integrated in a standard non-myeloablative conditioning regimen (3 days fludarabine 30 mg/m2 with 2 Gray total body irradiation (TBI)). Patients with AML ≥ 18 years in 1st (in)complete remission (CR/CRi) with a poor or very poor risk profile, as defined by the HOVON-132 protocol, were eligible. Results: Forty-six patients (median age 60; range 23-74) were included. Median follow up time was 44 months (range 31-65 months). The cumulative 1-year incidence of relapse and NRM were respectively 23% and 11%. Incidence of grade III-IV acute graft-vs-host-disease (GVHD) and severe chronic GVHD were 13% and 20%, respectively. One-year OS was 70%. Application of ELN 2017 risk classification to the study cohort revealed a cumulative one-year relapse rate of respectively 31% and 13% for the adverse and intermediate risk patients. To conclude, the 10-day DEC/FLU/TBI conditioning regimen prior to allo HCT in poor risk AML patients is effective and feasible.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Bussulfano , Decitabina , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Condicionamento Pré-Transplante/efeitos adversos , Vidarabina/análogos & derivados , Irradiação Corporal Total
19.
Anim Reprod Sci ; 228: 106746, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33819898

RESUMO

Busulfan is widely used in some species to inhibit germ cell proliferation. This study was conducted to evaluate effects of busulfan on germ and somatic cells in gonads of olive flounder, Paralichthys olivaceus, one of the most economically important mariculture fish species. After intraperitoneal injection with 80 (80B) or 120 (120B) mg/kg busulfan, both gonads were atrophied, and ovaries were discolored with adhesion to the visceral mass. Histological results indicated that germ cells in the gonads were detached, and there was a larger nucleus size and smaller cytoplasmic volume in spermatogonia. Numbers of oocytes and somatic cells in the ovary were both less (P < 0.05), while in the testis, numbers of spermatogonia and somatic cells were markedly lesser and greater, respectively (P < 0.05). In ovaries of the flounder treated with 80B and 120B, relative abundance of vasa and cyp19a1a mRNA transcripts was very small in the cytoplasm of oocytes, while the cyp19a1a transcript was still present in theca cells. In the testis of flounder treated with 80B and 120B, abundance of vasa was markedly less (P < 0.05) with there being very little vasa in spermatogonia and disruption of the spermatogonium structure. In the 80B treatment group, amh was in lesser abundance with there being very little amh in spermatogonia, however, with the 120B treatment there was a large amh abundance in spermatogonium with there being disruption of structure of these germ cells and Sertoli cells. Busulfan, therefore, might inhibit the development of spermatogonia in the flounder testis.


Assuntos
Bussulfano/farmacologia , Linguado , Ovário/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Testículo/efeitos dos fármacos , Alquilantes/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hibridização In Situ , Masculino , Ovário/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Maturidade Sexual , Testículo/citologia
20.
Sci Rep ; 11(1): 9127, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911174

RESUMO

Most transgenic animals are generated using a genome-modified stem cell system and genome modification directly in embryos. Although this system is well-established in the development of transgenic animals, donor cell-derived transgenic animal production is inefficient in some cases. Especially in avian models such as chickens, the efficiency of transgenic animal production through primordial germ cells (PGCs) is highly variable compared with embryonic manipulation of mammalian species. Because germ cell and germline-competent stem cell-mediated systems that contain the transgene are enriched only at the upstream level during cell cultivation, the efficiency of transgenic animal production is unreliable. Therefore, we developed an in vivo selection model to enhance the efficiency of transgenic chicken production using microsomal glutathione-S-transferase II (MGSTII)-overexpressing PGCs that are resistant to the alkylating agent busulfan, which induces germ cell-specific cytotoxicity. Under in vitro conditions, MGSTII-tg PGCs were resistant to 1 µM busulfan, which was highly toxic to wild-type PGCs. In germline chimeric roosters, transgene-expressing germ cells were dominantly colonized in the recipient testes after busulfan exposure compared with non-treated germline chimera. In validation of germline transmission, donor PGC-derived progeny production efficiency was 94.68%, and the transgene production rate of heterozygous transgenic chickens was significantly increased in chickens that received 40 mg/kg busulfan (80.33-95.23%) compared with that of non-treated germline chimeras (51.18%). This system is expected to significantly improve the efficiency of generating transgenic chickens and other animal species by increasing the distribution of donor cells in adult testes.


Assuntos
Alquilantes/farmacologia , Animais Geneticamente Modificados/genética , Bussulfano/farmacologia , Galinhas/genética , Resistência a Medicamentos/efeitos dos fármacos , Animais , Células Germinativas/citologia , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Glutationa Transferase/genética , Heterozigoto , Microssomos/metabolismo , Modelos Animais
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