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1.
Genes Chromosomes Cancer ; 62(4): 202-209, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36448876

RESUMO

The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%-40% of cases. Novel genetic factors for pediatric AML need to be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF-ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF-ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF-ITDs were found in exon 13 and shared a duplicated region. UBTF-ITD was more frequently detected in patients with trisomy 8, FLT3-ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3-ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF-ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML-05 cohort revealed that patients with UBTF-ITD had worse outcomes than those without UBTF-ITD (3-year event-free survival, 20% vs. 55%; 3-year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF -ITD had a poor prognosis resulting in early events (relapse or non-complete remission) within 1 year. Our findings suggest that UBTF-ITD may be a novel and significant prognostic factor for pediatric patients with AML.


Assuntos
Leucemia Mieloide Aguda , Adulto , Criança , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Prognóstico , Recidiva , Trissomia
2.
Genes Chromosomes Cancer ; 62(7): 412-422, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37102302

RESUMO

Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML.


Assuntos
Leucemia Mieloide Aguda , Humanos , Criança , Mutação , Leucemia Mieloide Aguda/patologia , Prognóstico , Estimativa de Kaplan-Meier , Proteína Supressora de Tumor p53/genética , Transportador de Glucose Tipo 5/genética , Ubiquitina-Proteína Ligases/genética , Proteínas de Ligação a Retinoblastoma/genética
3.
Jpn J Clin Oncol ; 48(7): 684-691, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860341

RESUMO

B-cell precursor acute lymphoblastic leukemia is the most common pediatric malignancy, but its treatment needs to be modified to cause low acute toxicity and few late complications with a high cure rate. In this trial, we will stratify patients with B-cell precursor acute lymphoblastic leukemia into standard, intermediate and high risk groups according to prognostic factors. In addition, we will establish an evaluation system for minimal residual disease that will enable us to stratify patients based on minimal residual disease in subsequent clinical trials. We will clarify the impact of dexamethasone/vincristine pulse therapy during maintenance therapy in the standard risk group, and intensive l-asparaginase therapy in the intermediate risk group. In the high risk group, usefulness of vincristine intensification will be assessed. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000009339 [http://www.umin.ac.jp/ctr/].


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Determinação de Ponto Final , Feminino , Humanos , Lactente , Japão , Masculino , Tamanho da Amostra , Resultado do Tratamento
4.
Pediatr Blood Cancer ; 64(8)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28084041

RESUMO

BACKGROUND: In the tyrosine kinase inhibitor (TKI) era, outcomes after salvage therapy for relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remain unclear. PROCEDURE: The clinical courses of 19 patients with relapse (n = 13) or induction failure (n = 6) in the Japanese Pediatric Leukemia/Lymphoma Study Group Ph+ ALL04 study were retrospectively reviewed. RESULTS: Fifteen male and four female patients had a median age of 8 (range 4-15) years at relapse or induction failure. Patients received imatinib in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and methotrexate and cytarabine (MTX/Ara-C) (n = 9), imatinib in combination with other chemotherapy (n = 5), chemotherapy without imatinib (n = 2), imatinib alone (n = 2), or no additional chemotherapy (n = 1). Two patients underwent hematopoietic stem cell transplantation (HSCT) without achieving complete remission (CR) and died of leukemia. The remaining 17 patients achieved CR with salvage therapies and underwent HSCT whilst in CR: 10 patients remain alive in CR, five died of transplantation-related complications, and two died of relapse. In six of seven patients with available data on minimal residual disease (MRD), imatinib in combination with the first course of hyper-CVAD was more effective in achieving a favorable MRD response compared with the Ph+ ALL04 induction regimen. CONCLUSION: This study suggested that cross-resistance to imatinib failed to develop after conventional chemotherapy. Imatinib in combination with chemotherapy including hyper-CVAD+MTX/Ara-C was effective and safe for relapsed or refractory Ph+ ALL patients who received frontline therapy without imatinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mesilato de Imatinib/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de Salvação/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/terapia , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Retrospectivos
5.
Pediatr Int ; 59(2): 145-153, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27422759

RESUMO

BACKGROUND: Quality of life (QOL) as a treatment outcome has not yet been evaluated among patients receiving a specific treatment regimen by treatment phase in a consistent manner. This exploratory cross-sectional study evaluated the QOL of children with acute lymphoblastic leukemia (ALL) receiving one of the most popular treatment regimens in Japan (Japan Association of Childhood Leukemia Study ALL-02 revised protocol). METHODS: Children aged 5-18 years with newly diagnosed B-cell precursor ALL were included. The Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales (PedsQL-J) were completed by children with ALL and their siblings, as well as by age- and sex-matched healthy controls. PedsQL Cancer Module (PedsQL-C) scores were also collected from children with ALL. RESULTS: QOL in children with ALL of the consolidation phase group was significantly decreased compared with that of healthy controls, except in the area of emotional functioning. Regarding the maintenance phase group, QOL impairment was noted in the physical and school functioning, but no differences were noted in social functioning. The off-treatment group had a large effect size only for physical functioning, and the social functioning score was even better in children with ALL than in matched controls. QOL of children with ALL differed with treatment phase. Effect size varied with function and treatment phase. CONCLUSIONS: QOL may change with the progression of treatment, and the timing of these changes varied according to function and problem.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Indicadores Básicos de Saúde , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Qualidade de Vida , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Autorrelato , Resultado do Tratamento
6.
Genes Chromosomes Cancer ; 53(10): 815-23, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24935070

RESUMO

For an overall characterization of pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis of CRLF2 in 167 pediatric BCPALL patients. CRLF2 OE was detected in 30 (18%) of 167 patients, the P2RY8-CRLF2 fusion was identified in only 3 (1.8%) of 167 patients, all of which demonstrated CRLF2 OE. Moreover, CRLF2 gain was identified in 18 (11%) of 167 patients. Messenger RNA sequencing revealed a novel fusion transcript, CSF2RA-CRLF2, in a case with CRLF2 OE, suggesting that this fusion is associated with CRLF2 OE. In survival analysis, no significant differences in 5-year event-free survival (EFS) and overall survival were observed between patients with and without CRLF2 OE (70.7 vs. 75.4%, log rank P = 0.68 and 96.4 vs. 82.1%, log rank P = 0.11, respectively). However, a significant difference in 5-year EFS between CRLF2 OE patients with and without IKZF1 deletion was observed (44.4 vs. 83.1%, log rank P = 0.02). In multivariate analysis, only IKZF1 deletion was a significant predictor of inferior OS (hazard ratio: 2.427, P = 0.04).These findings suggest that CRLF2 OE is not an independent prognostic factor in pediatric BCPALL.


Assuntos
Pediatria , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores de Citocinas/genética , Adolescente , Criança , Pré-Escolar , Feminino , Fusão Gênica , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Receptores de Citocinas/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Análise de Sobrevida
7.
Tohoku J Exp Med ; 234(4): 309-12, 2014 12.
Artigo em Inglês | MEDLINE | ID: mdl-25504019

RESUMO

Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H(+)-ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two-nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertensão Pulmonar/etiologia , Osteopetrose/etiologia , Sequência de Bases , Análise Mutacional de DNA , Evolução Fatal , Humanos , Hipertensão Pulmonar/complicações , Lactente , Masculino , Dados de Sequência Molecular , Osteopetrose/complicações , Mudanças Depois da Morte , Artéria Pulmonar/patologia , ATPases Vacuolares Próton-Translocadoras/genética
9.
J Pediatr Hematol Oncol ; 35(7): e317-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23619112

RESUMO

There is considerable overlap between hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) in terms of aberrant immune response though the etiology of KD remains unknown. We present a case fulfilling the criteria of both HLH and KD complicated by coronary artery dilatation: HLH was confirmed to be triggered by Epstein-Barr virus. This case alarms us the possibility that even patients with HLH may be complicated by coronary artery lesion, which is one of the hallmarks of KD. We would like to draw attention that if features of KD become apparent in patients with HLH, echocardiographic examinations should be performed not to miss coronary artery lesion.


Assuntos
Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Medula Óssea/patologia , Pré-Escolar , Vasos Coronários/patologia , Ecocardiografia , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4 , Humanos , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/virologia , Resultado do Tratamento
11.
Int J Hematol ; 116(1): 131-138, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35349077

RESUMO

Ponatinib is effective in adults with Philadelphia chromosome-positive (Ph+) leukemia, resistant or intolerant to second-generation tyrosine kinase inhibitors, but there are limited data on its use in children. The clinical courses of nine pediatric patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) and four with chronic myeloid leukemia (CML) who received ponatinib therapy were retrospectively reviewed. The median age at the start of ponatinib therapy was 12 years (range 8-16 years). Nine patients were male and four were female. Six patients received ponatinib alone, three received ponatinib with prednisolone, one received ponatinib with rituximab intrathecal therapy, and one received ponatinib with conventional chemotherapy. Two patients received ponatinib both alone and in combination with chemotherapy. The median dose and duration of ponatinib were 16.9 mg/m2 (7-34.3) and 1.1 months (0.2-22.7), respectively. Six patients with Ph+ ALL and two with CML responded to ponatinib. One of the eight patients who received ponatinib alone had grade 4 increased lipase levels. Grade 3 non-hematologic toxicities included elevated alanine aminotransferase levels (25%), elevated aspartate aminotransferase levels (25%), elevated gamma-glutamyl transferase levels (12.5%), hypertension (12.5%), and polymorphic erythema (12.5%). Ponatinib may be safe and effective in pediatric patients with Ph+ leukemia.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Criança , Feminino , Humanos , Imidazóis , Japão , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas , Estudos Retrospectivos
12.
Int J Hematol ; 115(6): 890-897, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35258855

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. As overall cure rates of childhood ALL have improved, reduction of overall treatment intensity while still ensuring excellent outcomes is imperative for low-risk patients. We report the outcomes of patients treated following the standard-risk protocol from the prospective Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study, which was conducted between 2002 and 2008 for patients with newly diagnosed ALL aged 1-18 years. Of 1138 patients with B-cell precursor ALL, 388 (34.1%) were allocated to this protocol. Excellent outcomes were achieved despite the overall treatment intensity being lower than that of most contemporary protocols: 4 years event-free survival (EFS) was 92.3% and 4 years overall survival 98.2%. Patients with high hyperdiploidy (HHD) involving triple trisomy (trisomy of chromosomes 4, 10, and 17) or ETV6-RUNX1 had even better outcomes (4 years EFS 97.6% and 100%, respectively). Unique characteristics of this protocol include a selection of low-risk patients with a low initial WBC count and good early treatment response and reduction of cumulative doses of chemotherapeutic agents while maintaining dose density. In Japan, we are currently investigating the feasibility of this protocol while incorporating minimal residual disease into the patient stratification strategy.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Trissomia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Humanos , Lactente , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Prospectivos , Resultado do Tratamento
13.
Blood Cancer J ; 10(2): 23, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107374

RESUMO

This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/mortalidade , Irradiação Craniana/mortalidade , Recidiva Local de Neoplasia/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Risco Ajustado/métodos , Adolescente , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Taxa de Sobrevida
14.
Int J Hematol ; 109(4): 477-482, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30689137

RESUMO

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.


Assuntos
Asparaginase/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prednisolona/administração & dosagem , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Medição de Risco , Taxa de Sobrevida
15.
Int J Hematol ; 108(1): 91-97, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29574603

RESUMO

Therapy-related leukemia (t-leukemia) is associated with dismal prognosis. Published pediatric t-leukemia data are somewhat outdated and may not reflect recent advances in treatment. We report a retrospective nationwide survey of patients diagnosed between 2000 and 2013 in Japan. We identified 43 patients with pediatric t-leukemia; 33 had t-acute myeloid leukemia (t-AML), eight had t-acute lymphoblastic leukemia (t-ALL) and two had t-acute undifferentiated leukemia. Median age at onset and latency were 12 years and 3.8 years, respectively, consistent with previous reports. Of t-AML patients, 63.6% harbored topoisomerase II inhibitor (topo II)-related genetic abnormalities, while only 12.5% of t-ALL patients had such alterations, suggesting that topo II is not key to t-ALL leukemogenesis. The 7-year overall survival (OS) for all 43 patients was 39.2 ± 11.6%. The 5-year OS was 50 ± 20.4% in t-ALL, and 55.2 ± 11.0% in t-AML. Allogeneic hematopoietic cell transplantation (allo-HCT) was associated with superior 5-year OS (HCT(+) vs. HCT(-), 78.8 vs. 12.1%; p < 0.001), and 26 of 32 patients received allo-HCT in complete remission (CR). Only allo-HCT was associated with superior OS on multivariate analysis (HR 0.003, 95% CI 0.0001-0.098; p < 0.001). These findings suggest that allo-HCT in CR improves pediatric t-leukemia outcomes.


Assuntos
Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Idade de Início , Aloenxertos , Criança , Pré-Escolar , DNA Topoisomerases Tipo II/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Histona-Lisina N-Metiltransferase/genética , Humanos , Japão , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Estudos Retrospectivos , Inquéritos e Questionários , Taxa de Sobrevida , Fatores de Tempo , Inibidores da Topoisomerase II
16.
Int J Hematol ; 108(4): 438-442, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29971602

RESUMO

Myeloid sarcoma (MS) is a rare neoplastic condition that is often described in association with acute myeloid leukemia (AML). MS in childhood has received little attention, particularly in Japan. We carried out a nationwide retrospective analysis of Japanese children diagnosed with MS without bone marrow involvement. Inclusion criteria were diagnosis of MS at younger than 20 years of age between January 1, 2000 and December 31, 2013. There was a predominance of males (8:2), and the median age at MS diagnosis was 4 years. Sites of involvement varied and included skin (n = 3), head and/or neck (n = 2), and multiple sites (n = 2). Karyotypes were evaluated in seven patients, with one individual carrying t(8;21) and t(9;11). Four patients developed bone marrow involvement 2-55 months after diagnosis of MS. All patients received chemotherapy for de novo AML and two individuals received HSCT in first remission. Seven of ten patients survived for 50-152 months (median, 93 months) without disease after initial chemotherapy. This retrospective study confirmed that pediatric MS without bone marrow involvement in Japan is a very rare disease. MS patients responded favorably to therapies for de novo AML, and HSCT in first remission was not indicated for all patients.


Assuntos
Medula Óssea/patologia , Sarcoma Mieloide , Cariótipo Anormal , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Japão/epidemiologia , Masculino , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/tratamento farmacológico , Sarcoma Mieloide/mortalidade , Sarcoma Mieloide/patologia , Taxa de Sobrevida
17.
J Clin Oncol ; 36(9): 900-907, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29360413

RESUMO

Purpose Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL); however, data relating to ON in Asian pediatric patients with ALL are scarce. Therefore, we performed a retrospective analysis of cohorts of Japanese patients with ALL to clarify the incidence, clinical characteristics, and risk factors of ON. Patients and Methods The incidence and characteristics of ON were determined in patients with ALL (n = 1,662) enrolled in two studies from the Japan Association of Childhood Leukemia Study (JACLS) group (n = 635 and n = 1,027 patients treated with the ALL-97 and ALL-02 protocols, respectively). Results In total, 24 of 1,662 patients suffered from ON, of which 12 of 635 and 12 of 1,027 patients were treated with the ALL-97 and the ALL-02 protocol, respectively. Of the 24 patients, 23 were older than 10 years. In multivariate analysis, age (≥ 10 years) was the sole significant risk factor for ON ( P < .001). Separate evaluation of patients ≥ 10 years of age indicated a 5-year cumulative incidence of ON of 7.2% (95% CI, 4.0% to 12.6%) and 5.9% (95% CI, 3.3% to 10.4%) in the ALL-97 and the ALL-02 protocol, respectively, which was lower than reported previously, despite an administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and l-asparaginase was reduced in the JACLS protocols. Conclusion We identified a low frequency of ON in the JACLS ALL-97 and ALL-02 studies. Although the sole risk factor for ON was age (≥ 10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and l-asparaginase are administered, which affects the clearance of DEX, may be associated with ON incidence in patients with ALL.


Assuntos
Osteonecrose/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Estudos Multicêntricos como Assunto , Osteonecrose/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
18.
Int J Hematol ; 85(5): 371-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17562610

RESUMO

We propose a novel method for the efficient production of hematopoietic progenitors from human embryonic stem cells (hESC) via coculture with murine fetal liver-derived stromal cells, in which embryonic hematopoiesis dramatically expands at midgestation. We generated various hematopoietic progenitors in coculture, and this hematopoietic activity was concentrated in cobblestone-like cells derived from differentiated hESC. The cobblestone-like cells mostly expressed CD34 and retained an endothelial cell potential. They also contained hematopoietic colony-forming cells, especially erythroid and multilineage colony-forming cells at high frequency. The multipotential hematopoietic progenitors abundant among the cobblestone-like cells produced almost all types of mature blood cells, including adult-type alpha-globin-expressing erythrocytes and tryptase/chymase double-positive mast cells. These progenitors showed neither the immature properties of ESC nor the potential to differentiate into endoderm and ectoderm at a clonal level. The coculture system developed for hESC can provide a novel source of hematopoietic and blood cells for applications in cellular therapy and drug screening.


Assuntos
Técnicas de Cocultura/métodos , Hematopoese Extramedular , Células-Tronco Hematopoéticas/citologia , Células-Tronco Multipotentes/citologia , Animais , Diferenciação Celular , Divisão Celular , Células Cultivadas , Feminino , Humanos , Fígado/citologia , Fígado/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Células Estromais/citologia
19.
Int J Hematol ; 86(5): 446-50, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18192114

RESUMO

We describe the clinical course of a patient who experienced refractory pure red cell aplasia (PRCA) after undergoing HLA-matched allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for refractory anemia with an excess of blasts in transformation that had evolved from Kostmann syndrome. The treatment for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) developing from Kostmann syndrome has not been standardized. We treated this patient with allo-PBSCT using a regimen combining high-dose cytosine arabinoside with granulocyte colony-stimulating factor, in addition to total body irradiation and cyclophosphamide without preceding intensive chemotherapy. The donor was ABO incompatible. Myeloid and platelet recoveries were achieved rapidly. Erythroid engraftment was not evident, however, and the patient was given a diagnosis of PRCA. Regimen-related toxicity and graft-versus-host disease (GVHD) were limited. The PRCA did not respond to various therapies, including the discontinuation of immunosuppressants for the induction of chronic GVHD, human recombinant erythropoietin, immunosuppressive treatment with steroids, cyclosporin A, and human anti-CD20 antibody (rituximab). The patient received transfusions 48 times until the resolution of his anemia by donor leukocyte infusion (DLI) at 25 months after PBSCT. He is now clinically well (performance status, 100%) with normal blood cell counts at 5 years after SCT. An in vitro study demonstrated that serum from the recipient blocked the differentiation of erythroid cells in the bone marrow. The results indicate that the conditioning regimen we describe seems safe and effective for those who have MDS/AML and that DLI might be a valuable approach for refractory PRCA after ABO-incompatible SCT.


Assuntos
Transfusão de Leucócitos , Doadores Vivos , Síndromes Mielodisplásicas/terapia , Mielopoese , Transplante de Células-Tronco de Sangue Periférico , Aplasia Pura de Série Vermelha/terapia , Criança , Ciclofosfamida/administração & dosagem , Sobrevivência de Enxerto , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Imunossupressores/administração & dosagem , Lactente , Masculino , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/complicações , Proteínas Recombinantes , Aplasia Pura de Série Vermelha/etiologia , Indução de Remissão , Síndrome , Transplante Homólogo , Irradiação Corporal Total
20.
Cancer Med ; 4(5): 682-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25641907

RESUMO

Incorporation of imatinib into chemotherapeutic regimens has improved the prognosis of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). We investigated a role of imatinib immediately before hematopoietic stem cell transplantation (HSCT). Children with Ph(+) ALL were enrolled on JPLSG Ph(+) ALL 04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of Induction phase, Consolidation phase, Reinduction phase, 2 weeks of imatinib monotherapy phase, and HSCT phase (Etoposide+CY+TBI conditioning). Minimal residual disease (MRD), the amount of BCR-ABL transcripts, was measured with the real-time PCR method. The study was registered in UMIN-CTR: UMIN ID C000000290. Forty-two patients were registered and 36 patients (86%) achieved complete remission (CR). Eight of 17 patients (47%) who had detectable MRD at the beginning of imatinib monotherapy phase showed disappearance or decrease in MRD after imatinib treatment. Consequently, 26 patients received HSCT in the first CR and all the patients had engraftment and no patients died because of complications of HSCT. The 4-year event-free survival rates and overall survival rates among all the 42 patients were 54.1 ± 7.8% and 78.1 ± 6.5%, respectively. Four of six patients who did achieve CR and three of six who relapsed before HSCT were salvaged with imatinib-containing chemotherapy and subsequently treated with HSCT. The survival rate was excellent in this study although all patients received HSCT. A longer use of imatinib concurrently with chemotherapy should eliminate HSCT in a subset of patients with a rapid clearance of the disease.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mesilato de Imatinib/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Indução de Remissão , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento
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