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1.
Rinsho Ketsueki ; 62(8): 954-966, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497236

RESUMO

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Tirosina Quinase 3 Semelhante a fms/genética
2.
Rinsho Ketsueki ; 62(3): 157-162, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33828007

RESUMO

Bacillus cereus bacteremia is an infectious disease that may sometimes be fatal with a rapid clinical course. We performed a retrospective analysis on 12 patients with Bacillus cereus bacteremia recruited from January 2010 to March 2015. The primary diseases were acute leukemia (n=5), myelodysplastic syndromes (n=3), malignant lymphoma (n=3), and hemophagocytic syndrome (n=1). Neutrophil count at the onset of this bacteremia was less than 500 cells/µl in 9 patients. At the onset of bacteremia, we observed neurological symptoms (n=7), gastrointestinal symptoms (n=6), and findings suspected of infection at the venous catheter insertion site (n=6). Vancomycin was administered to all the patients; 10 patients showed improvement whereas 2 died early after allogeneic hematopoietic stem cell transplantation owing to bacteremia. Three patients had sequelae of central nervous system disorders. Neurological and gastrointestinal symptoms with fever may be predictors for this bacteremia, and early administration of appropriate antibacterial drugs may improve the prognosis. Future research should be aimed toward the identification of the clinical features of poor prognosis and establishment of remedies for Bacillus cereus bacteremia.


Assuntos
Bacteriemia , Doenças Hematológicas , Antibacterianos/uso terapêutico , Bacillus cereus , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Humanos , Estudos Retrospectivos
3.
Cancer Sci ; 111(7): 2472-2481, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32391628

RESUMO

In this phase II multicenter study (JALSG AML209-FLT3-SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) for FLT3-internal tandem duplication (ITD)-positive AML. Newly diagnosed de novo AML patients with FLT3-ITD were enrolled at the achievement of CR1 and received allo-HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17-49) years, 36 (75%) received allo-HSCT at a median of 108 days after CR1. The median follow-up was 1726 days. The primary end-point, 3-year disease-free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%-57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3-year overall survival, post-transplant DFS, and non-relapse mortality rates were 54.2% (95% CI, 39%-67%), 58.3% (95% CI, 41%-72%), and 25.0% (95% CI, 12%-40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006-4.099). Neither FLT3-ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo-HSCT for FLT3-ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.


Assuntos
Expansão das Repetições de DNA , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
4.
Blood Adv ; 4(1): 66-75, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31899799

RESUMO

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-kit/genética , Adolescente , Adulto , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Cadeias Pesadas de Miosina/genética , Prognóstico , Estudos Prospectivos , Proteína 1 Parceira de Translocação de RUNX1/genética , Adulto Jovem
5.
Cancer Sci ; 111(2): 312-322, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31821677

RESUMO

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3-TKD). Both mutant FLT3 molecules are activated through ligand-independent dimerization and trans-phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti-apoptosis. Because high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/genética , Mutação Puntual , Domínios Proteicos , Inibidores de Proteínas Quinases/farmacologia , Duplicações Segmentares Genômicas , Deleção de Sequência , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/química
6.
Ann Hematol ; 98(1): 83-91, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30251205

RESUMO

We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Proteína 1 Parceira de Translocação de RUNX1 , Proteínas Repressoras , Fatores de Transcrição , Translocação Genética , Adolescente , Adulto , Idoso , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/biossíntese , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Taxa de Sobrevida , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
7.
PLoS One ; 13(10): e0204850, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289902

RESUMO

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are essential for acute promyelocytic leukemia (APL) treatment. It has been reported that mutations in PML-RARA confer resistance to ATRA and ATO, and are associated with poor prognosis. Although most PML-RARA mutations were point mutations, we identified a novel seven amino acid deletion mutation (p.K227_T233del) in the RARA region of PML-RARA in a refractory APL patient. Here, we analyzed the evolution of the mutated clone and demonstrated the resistance of the mutated clone to retinoic acid (RA). Mutation analysis of PML-RARA was performed using samples from a chemotherapy- and ATRA-resistant APL patient, and the frequencies of mutated PML-RARA transcript were analyzed by targeted deep sequencing. To clarify the biological significance of the identified PML-RARA mutations, we analyzed the ATRA-induced differentiation and PML nuclear body formation in mutant PML-RARA-transduced HL-60 cells. At molecular relapse, the p.K227_T233del deletion and the p.R217S point-mutation in the RARA region of PML-RARA were identified, and their frequencies increased after re-induction therapy with another type of retinoiec acid (RA), tamibarotene. In deletion PML-RARA-transduced cells, the CD11b expression levels and NBT reducing ability were significantly decreased compared with control cells and the formation of PML nuclear bodies was rarely observed after RA treatment. These results indicate that this deletion mutation was closely associated with the disease progression during RA treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Promielocítica Aguda/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Tretinoína/farmacologia , Antígeno CD11b/genética , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Mutação Puntual , Deleção de Sequência
8.
Int J Hematol ; 108(3): 298-305, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29959747

RESUMO

There are few established therapies for chronic graft-versus-host disease (cGVHD) refractory to first-line treatment with steroids. We evaluated the efficacy and safety of extracorporeal photopheresis (ECP) with a third-generation TC-V device in Japanese patients with cGVHD. Fifteen patients with steroid-resistant or -intolerant cGVHD after allogeneic hematopoietic stem cell transplantation participated in this multicenter open-label study. Extracorporeal photopheresis was conducted on days 1-3, week 1; days 1-2, weeks 2-12; and days 1-2, weeks 16, 20, and 24. The composite primary endpoint consisted of evaluation of response and changes in steroid dose 24 weeks after ECP initiation. Secondary endpoints included response over time, concomitant drug dose, quality of life, and safety. Twelve patients completed scheduled ECP therapy; eight (66.7%) showed a response at week 24. In all 15 patients, the mean (± standard deviation) steroid dose decreased 0.115 ± 0.230 mg/kg/day from screening to week 24. Five serious, potentially treatment-related adverse events (heart failure, thrombosis in the device, pneumonia, edema, and wheezing) occurred; none were fatal. This study confirmed that ECP using the TC-V device was effective, with an acceptable toxicity profile. Further studies in larger cohorts are clearly warranted to determine its optimal use in Japanese patients with cGVHD.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Fotoferese/instrumentação , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Doença Crônica , Resistência a Medicamentos , Feminino , Glucocorticoides/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Fotoferese/efeitos adversos , Fotoferese/métodos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
9.
Int J Hematol ; 108(3): 290-297, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29923123

RESUMO

Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk of readmission for complications. We sought to examine the association between HSCT hospital length of stay and the incidence of readmission and survival after discharge. We retrospectively reviewed the cases of 230 allo-HSCT recipients. The cumulative incidence of readmission with non-relapse transplant-related complications (including infections; acute and chronic GVHD; liver, lung, renal, or neurological complications; and haematological abnormalities) 2 years after the first discharge was 49.7% in patients with length of stay ≤ 100 days (n = 156), and 66.6% in patients with length of stay > 100 days (n = 74) (P = 0.02). The cumulative incidence of readmission with infections 2 years after first discharge was lower in the length of stay ≤ 100 days group than in the length of stay > 100 days patients (27.1 vs. 41.3%, P = 0.04). Length of stay > 100 days was the only risk factor identified that correlated positively with the rate of readmission for non-relapse transplant-related complications [relative risk (RR) 1.53; 95% confidence interval (CI) 1.08-2.18, P = 0.018] or infections [RR 1.64; CI 1.03-2.61; P = 0.038]. Close follow-up of patients with longer length of stay after allo-HSCT is advised.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Tempo de Internação , Readmissão do Paciente/estatística & dados numéricos , Adolescente , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade , Adulto Jovem
11.
Cancer Genet ; 222-223: 38-45, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29666007

RESUMO

We analyzed the genetic mutation status of 13 patients with therapy-related myeloid neoplasms (t-MN). Consistent with previous reports, t-MN cells preferentially acquired mutations in TP53 and epigenetic modifying genes, instead of mutations in tyrosine kinase and spliceosome genes. Furthermore, we compared the mutation status of three t-MN cells with each of the initial lymphoid malignant cells, and identified common mutations among t-MN and the initial malignant cells in two patients. In a patient who developed chronic myelomonocytic leukemia (CMML) after follicular lymphoma (FL), TET2 mutation was identified in both CMML and FL cells. Notably, the TET2 mutation was also identified in peripheral blood cells in the disease-free period with the same allelic frequency as CMML and FL cells, but not in a germ-line control, indicating that the TET2 mutation occurred somatically in the initiating clone for both malignant cells. On the other hand, a germ-line MYB mutation was identified in a patient who developed myelodysplastic syndromes (MDS) after FL. These results suggest that germ-line deposition and clonal hematopoiesis are closely associated with t-MN susceptibility; however, further analysis is necessary to clarify the mechanism required to provide the initiating clone with lineage commitment and clonal expansion.


Assuntos
Análise Mutacional de DNA/métodos , Predisposição Genética para Doença , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Segunda Neoplasia Primária/genética , Adulto , Idoso , Antineoplásicos/efeitos adversos , Proteínas de Ligação a DNA/genética , Epigênese Genética , Feminino , Efeito Fundador , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/etiologia , Prebióticos , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myb/genética , Spliceossomos/genética , Proteína Supressora de Tumor p53/genética , Adulto Jovem
12.
Int J Hematol ; 107(5): 551-558, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29374827

RESUMO

In allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors, delays in donor search are adversely associated with patient outcome. However, the optimal duration for either waiting for an unrelated donor or selecting alternative sources remains undetermined. Using data from the Japan Marrow Donor Program (JMDP) registry, we retrospectively analyzed 349 adult patients who had searched for unrelated donors. Two hundred and three patients received allo-HSCT from JMDP donors (Group A) with a median of 140 days required to identify a donor, 60 received allo-HSCT from alternative sources (Group B) after a median of 111.5 days at which point either all donor candidates had failed or the patient achieved a second or subsequent complete remission, and 77 suspended allo-HSCT (Group C) after a median of 310 days. The 5-year overall survival (OS) rate in Group A was superior to that of Group C (48.6 vs 38.5%, P = 0.001). Although Group B included more patients with high or very high disease risk index (DRI) at the time of allo-HSCT compared with Group A, the 5-year OS was not significantly different between Groups A and B (48.6 vs 40.9%, P = 0.07), indicating that switching to alternative donors may benefit patients with high DRI.


Assuntos
Seleção do Doador , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Obtenção de Tecidos e Órgãos/métodos , Doadores não Relacionados , Adolescente , Adulto , Idoso , Aloenxertos , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Listas de Espera , Adulto Jovem
13.
Int J Hematol ; 107(2): 211-221, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29027623

RESUMO

The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Doadores não Relacionados , Adolescente , Adulto , Idoso , Doença Crônica , Estudos de Viabilidade , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tacrolimo/administração & dosagem , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Adulto Jovem
14.
Biol Blood Marrow Transplant ; 24(1): 43-49, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28860001

RESUMO

Late graft failure (LGF) without evidence of residual recipient cells is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-SCT) and often requires stem cell infusion from the same donor when the patient fails to respond to conventional therapies. We screened the peripheral blood (PB) of 14 patients who developed donor-type LGF at 2 to 132 months after allo-SCT for the presence of the markers for immune-mediated bone marrow (BM) failure. Increased glycosylphosphatidyl inositol-anchored protein-deficient (GPI-AP-) leukocytes, which accounted for .009% to 0.147% of the total granulocytes, were detected in 5 patients (severe aplastic anemia, n = 2; follicular lymphoma, n = 1; acute lymphoblastic leukemia, n = 1; myelodysplastic syndromes; n = 1) and 4.7% to 81.2% HLA-allele-lacking leukocytes (HLA-LLs) were detected in 2 patients (acute myelogenous leukemia, n = 1; and myelodysplastic syndromes, n = 1). Three of the 5 patients with increased GPI-AP- leukocytes were treated with antithymocyte globulin (ATG), and 2 patients achieved transfusion independence. These results suggest that immune mechanisms that are similar to acquired aplastic anemia underlie condition of approximately one-half of the patients with donor-type LGF, and that in patients with increased GPI-AP- cells, donor-derived hematopoiesis may be restored by ATG therapy alone without donor stem cell infusion.


Assuntos
Quimerismo , Rejeição de Enxerto/etiologia , Transplante Homólogo/efeitos adversos , Adulto , Soro Antilinfocitário/uso terapêutico , Feminino , Proteínas Ligadas por GPI/metabolismo , Rejeição de Enxerto/imunologia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
15.
Medicine (Baltimore) ; 96(50): e9160, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29390324

RESUMO

RATIONALE: Patients with the e6a2 BCR-ABL transcript, 1 of the atypical transcripts, have been reported to have a poor prognosis, and allogeneic stem cell transplantation (ASCT) can be considered as additional therapy. However, long-term survival after ASCT for this disease is rare. PATIENT CONCERNS: This report concerns a 55-year-old female patient with e6a2 BCR-ABL-positive acute myeloid leukemia including the outcome of ASCT followed by donor lymphocyte infusion (DLI). DIAGNOSES: The breakpoint was confirmed by direct sequencing. Her minimal residual disease could be detected by nested reverse-transcription polymerase chain reaction using primers for the minor BCR-ABL (e1a2) transcript. INTERVENTIONS: Treatment with tyrosine kinase inhibitors (TKIs) and ASCT followed by DLI. OUTCOMES: Despite multiple cytogenetic and molecular relapses after ASCT, she remains in molecular remission at 46 months after ASCT. LESSONS: This case indicates the efficacy of the combination of the graft-versus-leukemia effect and TKIs for e6a2 BCR-ABL-positive acute leukemia. When the Philadelphia chromosome with an unusual chromosomal breakpoint is suggested, we should clarify the breakpoint because that information can aid molecular assessments and decisions to provide an additional or alternative therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Feminino , Proteínas de Fusão bcr-abl , Efeito Enxerto vs Leucemia , Humanos , Transfusão de Linfócitos , Pessoa de Meia-Idade , Neoplasia Residual , Cromossomo Filadélfia , Proteínas Tirosina Quinases/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
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
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