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1.
Cancer Sci ; 115(6): 2002-2011, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38498976

RESUMO

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Transplante de Células-Tronco Hematopoéticas , Lenalidomida , Mieloma Múltiplo , Transplante Autólogo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Quimioterapia de Consolidação/métodos , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Oligopeptídeos/uso terapêutico , Oligopeptídeos/administração & dosagem , Quimioterapia de Indução/métodos , Intervalo Livre de Progressão , Adulto Jovem , Quimioterapia de Manutenção/métodos
2.
Bone Marrow Transplant ; 59(3): 344-349, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38114645

RESUMO

Posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been increasingly used in HLA-haploidentical transplantation and recent studies also demonstrated the efficacy of PTCy in HLA-matched transplantation. We conducted a prospective multicenter phase II study to evaluate the safety and efficacy of PTCy with tacrolimus and mycophenolate mofetil in 43 patients who underwent HLA-matched (n = 21), 1 allele mismatched (n = 20), or 2 allele mismatched (n = 2) peripheral blood stem cell transplantation (PBSCT) following myeloablative (n = 28) or reduced-intensity (n = 15) conditioning. The incidence of grade III-IV acute GVHD at 100 days was 2.3%. The incidences of grades II-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 16.3%, 14.0%, and 4.7%, respectively. Overall survival, disease-free survival, and non-relapse mortality at 2 years were 75.3%, 74.0%, and 7.0%, respectively. GVHD-free, relapse-free survival at 2 years was 67.0%. The rate of off-immunosuppressants in patients who survived without relapse at 2 years was 85.4%. These results indicate that PTCy is a valid option for GVHD prophylaxis in both HLA-matched and HLA 1-2 allele mismatched PBSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Humanos , Transplante de Células-Tronco de Sangue Periférico/métodos , Estudos Prospectivos , Alelos , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doadores não Relacionados
3.
Int J Hematol ; 115(2): 198-207, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34773575

RESUMO

INTRODUCTION: Primary myelofibrosis (PMF) is a clonal stem cell disorder characterized by myeloid dominant hematopoiesis and dysregulated proliferation of fibroblasts in the bone marrow. However, how these aberrant myeloid cells and fibroblasts are produced remains unclear. AIM AND METHODS: In this study, we examined in vivo engraftment kinetics of PMF patient-derived CD34+ cells in immunecompromised NOD/SCID/IL2rgKO (NSG) mice. Engrafted human cells were analyzed with flow cytometry, and proliferation of fibroblastic cells and bone marrow fibrosis were assessed with the histo-pathological examination. RESULTS: Transplantation of PMF patient-derived circulating CD34+ fractions into NSG newborns recapitulates clinical features of human PMF. Engraftment of human CD45+ leukocytes resulted in anemia and myeloid hyperplasia accompanied by bone marrow fibrosis by six months post-transplantation. Fibrotic bone marrow contained CD45-vimentin+ cells of both human and mouse origin, suggesting that circulating malignant CD34+ subsets contribute to myelofibrotic changes in PMF through direct and indirect mechanisms. CONCLUSION: A patient-derived xenotransplantation (PDX) model of PMF allows in vivo examination of disease onset and propagation originating from immature CD34+ cells and will support the investigation of pathogenesis and development of therapeutic modalities for the disorder.


Assuntos
Antígenos CD34/análise , Medula Óssea/patologia , Hematopoese , Células Mieloides/patologia , Mielofibrose Primária/patologia , Animais , Antígenos CD34/sangue , Células Cultivadas , Fibrose , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Mielofibrose Primária/sangue
4.
Bone Marrow Transplant ; 56(1): 129-136, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32624582

RESUMO

Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Soro Antilinfocitário , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Pessoa de Meia-Idade , Condicionamento Pré-Transplante
5.
Bone Marrow Transplant ; 56(3): 596-604, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32973350

RESUMO

Posttransplant cyclophosphamide (PTCy:100 mg/kg) has been increasingly used in allogeneic hematopoietic stem cell transplantation, however, few studies compared different doses of PTCy. We conducted two consecutive prospective multicenter phase II studies to evaluate the safety and efficacy of 80 mg/kg of PTCy in 137 patients who underwent HLA-haploidentical peripheral blood stem cell transplantation (haploPBSCT) following reduced-intensity conditioning (RIC). GVHD prophylaxis consisted of PTCy at a dose of 40 mg/kg/day on days 3 and 4, tacrolimus, and mycophenolate mofetil. Neutrophil engraftment was achieved in 97% and 96% in the first and second studies, respectively. The incidences of grades II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 26%, 5%, 35%, and 18% in the first study, and 23%, 1%, 28%, and 15% in the second study, respectively. Overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) at 2 years were 51%, 42%, and 18% in the first study, and 58%, 48%, and 16% in the second study, respectively. The rates of off-immunosuppressants in patients who survived without relapse at 2 years were 83 and 76%. Our results suggest that 80 mg/kg of PTCy is a valid option in haploPBSCT following RIC.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Ciclofosfamida , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Estudos Prospectivos , Condicionamento Pré-Transplante
6.
Int J Hematol ; 112(4): 510-523, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32656637

RESUMO

An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54 years (median age, 61 years; range 55-70 years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8 mg/kg) along with fludarabine (180 mg/m2) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2 years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2 years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.


Assuntos
Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Fatores Etários , Idoso , Bussulfano/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Estudos Prospectivos , Doses de Radiação , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal Total/métodos
7.
Geriatr Gerontol Int ; 19(10): 988-992, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31397034

RESUMO

AIM: Red cell distribution width (RDW) is a simple, sensitive and cost-effective parameter, and is associated with pathophysiology of many common diseases. The aim of the present study was to investigate the prognostic role of RDW in older adults hospitalized for the treatment of heart failure (HF) or infection, because both diseases are fatal, especially in the geriatric population. METHODS: This observational study consecutively enrolled 196 Japanese older (aged ≥75 years) patients hospitalized for the treatment of HF (group A, n = 102) or non-cardiovascular bacterial infection (group B, n = 94). Baseline and clinical data were extracted from medical records. The observational period was that of hospitalization. The primary end-point was classified in the order of discharge to the patients' home, discharge to other facilities and in-hospital death. RESULTS: Longer hospital stay (P < 0.01) and worse prognosis (P < 0.01), including higher in-hospital mortality, were found in patients showing RDW ≥15% relative to those with RDW <15% in both groups. RDW showed no in-hospital variation despite successful treatment of acutely decompensated HF in selected patients of group A (n = 64). CONCLUSIONS: The present study showed the role of RDW in predicting the prognostic outcome of older adults hospitalized for the treatment of HF or infection, indicating that RDW is a stable and reliable parameter in these common diseases. Geriatr Gerontol Int 2019; 19: 988-992.


Assuntos
Índices de Eritrócitos , Insuficiência Cardíaca , Infecções , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar , Hospitalização , Humanos , Infecções/sangue , Infecções/mortalidade , Tempo de Internação , Masculino , Prognóstico
8.
Int J Clin Oncol ; 24(8): 966-975, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30937622

RESUMO

BACKGROUND: The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance. METHODS: Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year. RESULTS: Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group. CONCLUSIONS: The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/terapia , Terapia Neoadjuvante/métodos , Transplante de Células-Tronco/métodos , Adulto , Idoso , Bortezomib/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Japão , Lenalidomida/administração & dosagem , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Prognóstico , Taxa de Sobrevida , Talidomida/administração & dosagem , Transplante Autólogo
9.
Arthritis Res Ther ; 21(1): 30, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670057

RESUMO

BACKGROUND: The effectiveness of autologous haematopoietic stem cell transplantation (auto-HSCT) in treating severe systemic sclerosis (SSc) is established; however, the necessity of purified CD34+ cell grafts and the appropriate conditioning regimen remain unclear. This study aimed to compare the efficacy and safety of CD34-selected auto-HSCT with unmanipulated auto-HSCT to treat severe SSc. METHODS: This study was a post hoc analysis of a phase I/II clinical trial conducted in Japan. Nineteen patients with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilised with cyclophosphamide (4 g/m2) and filgrastim (10 µg/kg/day). Following PBSC collection by apheresis, CD34+ cells were immunologically selected in 11 patients. All patients were treated with high-dose cyclophosphamide (200 mg/kg) monotherapy as a conditioning regimen and received CD34-selected (n = 11) or unmanipulated auto-HSCT (n = 8). Changes in skin sclerosis and pulmonary function were assessed over an 8-year follow-up period. Differences in the changes, toxicity, progression-free survival (PFS) and overall survival were compared between patients who had received CD34-selected auto-HSCT and those who had received unmanipulated auto-HSCT. RESULTS: Skin sclerosis progressively improved after transplantation over an 8-year follow-up period in both groups, and the improvement was significantly greater in the CD34-selected group than in the unmanipulated group. Forced vital capacity in the CD34-selected group continuously increased over 8 years, whereas in the unmanipulated group it returned to baseline 3 years after transplantation. Toxicity and viral infections, such as cytomegalovirus infection and herpes zoster, were more frequently found in the CD34-selected group than in the unmanipulated group. The frequency of severe adverse events, such as bacterial infections or organ toxicity, was similar between the two groups. No treatment-related deaths occurred in either treatment group. PFS of the CD34-selected group was greater than that of the unmanipulated group, and the 5-year PFS rates of the CD34-selected and unmanipulated group were 81.8% and 50% respectively. CONCLUSIONS: CD34-selected auto-HSCT may produce favourable effects on improvement of skin sclerosis and pulmonary function compared with unmanipulated auto-HSCT. Use of CD34-selected auto-HSCT with high-dose cyclophosphamide monotherapy as a conditioning regimen may offer an excellent benefit-to-risk balance.


Assuntos
Antígenos CD34/sangue , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Escleroderma Sistêmico/terapia , Adulto , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Escleroderma Sistêmico/patologia , Índice de Gravidade de Doença , Condicionamento Pré-Transplante/métodos , Transplante Autólogo
10.
Int J Hematol ; 109(1): 107-114, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30284685

RESUMO

The efficacy and safety of lenalidomide (LEN) consolidation therapy and subsequent LEN maintenance therapy after high-dose therapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in patients with newly diagnosed symptomatic multiple myeloma (MM). Forty-one patients were enrolled and received high-dose dexamethasone (DEX) therapy as an initial induction. The patients who did not respond to the DEX therapy were further treated with four cycles of bortezomib plus DEX (BD) induction therapy. For patients who responded to BD, PBSC harvesting was scheduled following high-dose cyclophosphamide and filgrastim administration. After PBSC harvesting, high-dose chemotherapy of melphalan with auto-PBSCT was performed. One hundred days after auto-PBSCT, patients received consolidation therapy consisting two cycles of LEN plus low-dose DEX (Ld) and LEN maintenance therapy. Only one death occurred during mobilization therapy, but the protocol developed in this study was considered generally safe to provide. Overall response rates after consolidation and maintenance therapies were 73.7% and 81.6%, respectively. Two-year progression-free survival and overall survival were 76.3% and 92.1%, respectively. These observations suggest that LEN consolidation and maintenance therapy are effective and safe, and provide favorable response rates in patients with MM.


Assuntos
Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Bortezomib/uso terapêutico , Quimioterapia de Consolidação/métodos , Dexametasona/uso terapêutico , Quimioterapia de Manutenção/métodos , Melfalan/uso terapêutico , Mieloma Múltiplo/mortalidade , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
11.
Bone Marrow Transplant ; 54(3): 432-441, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30087460

RESUMO

We conducted two parallel prospective, multicenter, phase II studies to evaluate the safety and efficacy of HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) following myeloablative conditioning (MAC, n = 50) and reduced-intensity conditioning (RIC, n = 77). Event-free survival (EFS) at 1-year as for primary endpoint was 64% and 43% in the MAC and RIC groups, respectively. Neutrophil engraftment was achieved in 98% and 94% in the MAC and RIC groups, respectively. The incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 18% and 8% in the MAC group, and 14% and 5% in the RIC group, respectively. Those of all grade and moderate to severe chronic GVHD at 2-year were 36% and 20% in the MAC group, and 27% and 20% in the RIC group, respectively. Overall survival (OS), EFS, nonrelapse mortality, and relapse rate at 2-year were 68%, 54%, 10%, and 36% in the MAC group, and 44%, 35%, 20%, and 45% in the RIC group, respectively. Notably, 83% and 86% of patients who survived without relapse stopped immunosuppressant at 2-year in the MAC and RIC groups, respectively. Our results indicate that both MAC and RIC are valid options for PTCy-haploPBSCT for adults with hematological malignancies.


Assuntos
Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Ciclofosfamida/farmacologia , Feminino , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
12.
Int J Hematol ; 109(1): 131, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30406327

RESUMO

In the original publication of this article, "Conflict of interest" was published incorrectly. The corrected "Conflict of interest" is given below for your reading.

13.
Int J Hematol ; 107(4): 468-477, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29243031

RESUMO

We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65 years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n = 45) or ASCT arm (n = 42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p = 0.25). Three-year overall survival (OS) rates were 77 and 68% (p = 0.67). Incidence of relapse was 54 and 41% (p = 0.22). There was no significant difference in nonrelapse mortality between two arms (p = 0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
14.
Int J Hematol ; 103(6): 676-85, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27084252

RESUMO

To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15-60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Transplante de Células-Tronco de Sangue Periférico , Rituximab/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Transplante Autólogo , Resultado do Tratamento , Vincristina/uso terapêutico
16.
EBioMedicine ; 2(7): 744-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26288847

RESUMO

BACKGROUND: Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2). METHODS: Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese. FINDINGS: A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody. INTERPRETATION: The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans. FUNDING: Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.


Assuntos
Povo Asiático/genética , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , TYK2 Quinase/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Adulto Jovem
17.
Biol Blood Marrow Transplant ; 21(9): 1646-52, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26093044

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-SCT) using post-transplant cyclophosphamide (PTCy) is increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after busulfan-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT. Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) and chronic GVHD at 1 year were 23%, 3%, and 15%, respectively. No patients developed severe chronic GVHD. Day 100 nonrelapse mortality (NRM) rate was 19.4%. Overall survival, relapse, and disease-free survival rates were 45%, 45%, and 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of prior allo-SCT had lower engraftment, higher NRM, and lower overall survival than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after busulfan-containing reduced-intensity conditioning achieved low incidences of acute and chronic GVHD and NRM and stable donor engraftment and low NRM, particularly in patients without a history of prior allo-SCT.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Antígenos HLA , Neoplasias Hematológicas , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
18.
Gene ; 530(1): 19-25, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23954874

RESUMO

Although mutations of autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting a wide spectrum of many characteristic and non-characteristic clinical features, some patients lack AIRE gene mutations. Therefore, something other than a mutation, such as dysregulation of AIRE gene, may be a causal factor for APECED or its related diseases. However, regulatory mechanisms for AIRE gene expression and/or translation have still remained elusive. We found that IL-2-stimulated CD4(+) T (IL-2T) cells showed a high expression of AIRE gene, but very low AIRE protein production, while Epstein-Barr virus-transformed B (EBV-B) cells express both AIRE gene and AIRE protein. By using microarray analysis, we could identify miR-220b as a possible regulatory mechanism for AIRE gene translation in IL-2T cells. Here we report that miR-220b significantly reduced the expression of AIRE protein in AIRE gene with 3'UTR region transfected 293T cells, whereas no alteration of AIRE protein production was observed in the open reading frame of AIRE gene alone transfected cells. In addition, anti-miR-220b reversed the inhibitory function of miR-220b for the expression of AIRE protein in AIRE gene with 3'UTR region transfected cells. Moreover, when AIRE gene transfected cells with mutated 3'UTR were transfected with miR-220b, no reduction of AIRE protein production was observed. Taken together, it was concluded that miR-220b inhibited the AIRE gene translation through the 3'UTR region of AIRE gene, indicating that miR-220b could serve as a regulator for human AIRE gene translation.


Assuntos
Interleucina-2/metabolismo , MicroRNAs/genética , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Humanos , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/virologia , Biossíntese de Proteínas , Proteína AIRE
19.
Int J Hematol ; 98(2): 186-96, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23754766

RESUMO

We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5 years were 64.0 % (95 % CI 52.5-73.4) and 66.4 % (95 % CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103 months (range 3-240 months), respectively. Two patients died of transplant-related pulmonary complications 6 months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3 %, respectively, but there was no significant difference statistically among the risk groups (log-rank p = 0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.


Assuntos
Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Autoenxertos , Bussulfano/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida
20.
PLoS One ; 8(5): e62506, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23667482

RESUMO

BACKGROUND: Definite identification of the cell types and the mechanism relevant to cardiomyogenesis is essential for effective cardiac regenerative medicine. We aimed to identify the cell populations that can generate cardiomyocytes and to clarify whether generation of donor-marker(+) cardiomyocytes requires cell fusion between BM-derived cells and recipient cardiomyocytes. METHODOLOGY/PRINCIPAL FINDINGS: Purified BM stem/progenitor cells from green fluorescence protein (GFP) mice were transplanted into C57BL/6 mice or cyan fluorescence protein (CFP)-transgenic mice. Purified human hematopoietic stem cells (HSCs) from cord blood were transplanted into immune-compromised NOD/SCID/IL2rγ(null) mice. GFP(+) cells in the cardiac tissue were analyzed for the antigenecity of a cardiomyocyte by confocal microscopy following immunofluorescence staining. GFP(+) donor-derived cells, GFP(+)CFP(+) fused cells, and CFP(+) recipient-derived cells were distinguished by linear unmixing analysis. Hearts of xenogeneic recipients were evaluated for the expression of human cardiomyocyte genes by real-time quantitative polymerase chain reaction. In C57BL/6 recipients, Lin(-/low)CD45(+) hematopoietic cells generated greater number of GFP(+) cardiomyocytes than Lin(-/low)CD45(-) mesenchymal cells (37.0+/-23.9 vs 0.00+/-0.00 GFP(+) cardiomyocytes per a recipient, P = 0.0095). The number of transplanted purified HSCs (Lin(-/low)Sca-1(+) or Lin(-)Sca-1(+)c-Kit(+) or CD34(-)Lin(-)Sca-1(+)c-Kit(+)) showed correlation to the number of GFP(+) cardiomyocytes (P<0.05 in each cell fraction), and the incidence of GFP(+) cardiomyocytes per injected cell dose was greatest in CD34(-)Lin(-)Sca-1(+)c-Kit(+) recipients. Of the hematopoietic progenitors, total myeloid progenitors generated greater number of GFP(+) cardiomyocytes than common lymphoid progenitors (12.8+/-10.7 vs 0.67+/-1.00 GFP(+) cardiomyocytes per a recipient, P = 0.0021). In CFP recipients, all GFP(+) cardiomyocytes examined coexpressed CFP. Human troponin C and myosin heavy chain 6 transcripts were detected in the cardiac tissue of some of the xenogeneic recipients. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HSCs resulted in the generation of cardiomyocytes via myeloid intermediates by fusion-dependent mechanism. The use of myeloid derivatives as donor cells could potentially allow more effective cell-based therapy for cardiac repair.


Assuntos
Células da Medula Óssea/citologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Miócitos Cardíacos/citologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Fusão Celular , Linhagem da Célula , Sangue Fetal/citologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/citologia , Miócitos Cardíacos/metabolismo
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