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1.
Blood Cancer Discov ; 3(5): 410-427, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-35839275

RESUMO

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. SIGNIFICANCE: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.


Assuntos
Janus Quinase 2 , Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda , Receptores da Eritropoetina , Exoma , Humanos , Janus Quinase 2/genética , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Prognóstico , Receptores da Eritropoetina/genética
2.
Cancer Immunol Immunother ; 71(6): 1419-1430, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34677647

RESUMO

PURPOSE: Complete remission (CR) of acute myeloid leukemia (AML) in elderly patients has a short duration, and there is no suitable post-remission therapy. We explored the role of the Wilms' tumor 1 helper peptide OCV-501 to prevent recurrence after remission. METHODS: This placebo-controlled phase 2 study was designed to evaluate accurately the efficacy and immunogenicity of OCV-501 in elderly AML patients. Elderly AML patients who achieved first CR were randomly allocated to receive either OCV-501 (N = 69) or placebo (N = 65) once a week for eight weeks and then every two weeks until week 104. The primary endpoint was disease-free survival (DFS). RESULTS: Nineteen (27.5%) patients in the OCV-501 group and 23 (35.4%) patients in the placebo group completed the study without relapse. The median DFS in the OCV-501 and placebo groups was 12.1 and 8.4 months, respectively (p = 0.7671, hazard ratio [95% confidence interval]: 0.933 [0.590, 1.477]). The major drug adverse reactions were injection-site reactions. Although treatment with OCV-501 did not prolong DFS for elderly AML patients, post hoc analysis found that immune responders to OCV-501 whose specific IgG was > 10,000 ng/mL (N = 16) and whose WT1-specific interferon-γ response was > 10 pg/mL (N = 26) had significantly longer overall survival compared with placebo. CONCLUSIONS: The placebo-controlled design of this study and quantitative immunological monitoring provides new insight into the relationship between peptide-induced immune responses and survival, suggesting future perspectives for cancer immunotherapy.


Assuntos
Leucemia Mieloide Aguda , Proteínas WT1 , Idoso , Intervalo Livre de Doença , Humanos , Peptídeos , Indução de Remissão
3.
Int J Clin Oncol ; 26(11): 2131-2141, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34363558

RESUMO

BACKGROUND: Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). METHODS: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. RESULTS: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). CONCLUSION: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.


Assuntos
Leucemia Mieloide Aguda , Pirazinas , Compostos de Anilina , Humanos , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Tirosina Quinase 3 Semelhante a fms/genética
4.
Gan To Kagaku Ryoho ; 47(13): 1997-1999, 2020 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-33468779

RESUMO

AIM: To review the clinical features of the patient with cystic pulmonary light chain deposition disease(LCDD)and record high-resolution CT and histopathological findings. PATIENT: A 60-year-old woman who diagnosed multiple myeloma was admitted. There were diffuse proliferation of plasma cells by the bone marrow puncture that she received. And multiple cystic pulmonary tumors found in CT. We analyzed the method and result of the diagnosis. CT showed multiple cystic pulmonary tumors in the both lung which vessels traversing the cysts with thin wall ranged 5 to 30 millimeters. There were no abnormality in the heart, kidney and liver. Right upper lobe wedge resection was performed via video-assisted thoracic surgery( VATS)to establish a definitive diagnosis. Thoracoscopic findings revealed multiple white oval formed tumors in the visceral pleura. Histological HE staining findings of the surgical specimen revealed amyloid-like acidophilic material, and the immunohistochemical Congo red staining revealed monoclonal IgG with a kappa component. According to the above results these tumors had a diagnosis of pulmonary LCDD. CONCLUSION: VATS was effective to diagnose pulmonary LCDD in multiple cysts formation.


Assuntos
Cistos , Neoplasias Pulmonares , Mieloma Múltiplo , Cistos/cirurgia , Feminino , Humanos , Pulmão , Neoplasias Pulmonares/diagnóstico , Pessoa de Meia-Idade , Cirurgia Torácica Vídeoassistida
5.
Am J Case Rep ; 20: 780-784, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31155607

RESUMO

BACKGROUND Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma characterized by involvement of lymphoma cells in the lumina of small blood vessels in various organs. Although many studies have claimed that timely diagnosis and early initiation of chemotherapy are important, the literature on the successful treatment of IVLBCL in elderly patients over the age of 80 years is scarce. CASE REPORT An 82-year-old man presented with abnormal elevation of lactate dehydrogenase at 1605 IU/L and altered mental status, which manifested as forgetfulness, abnormal behavior, and worsening performance status for 2 days. There was no evidence of lymphadenopathy or skin lesions, but a computed tomography scan of the chest showed bilateral diffuse ground-glass opacities. With a primary consideration of IVLBCL, random skin biopsy and transbronchial lung biopsy were performed. Immediately after the pathologic findings on hematoxylin-eosin staining alone revealed abnormal large cells in the small vessels, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) at half the usual dose was started; later on, immunostaining revealed CD20 expression in the abnormal lymphoid cells. Immediately after CHOP administration, his mental and physical symptoms rapidly resolved. After 8 cycles of dose-reduced CHOP with rituximab, he remained free from disease progression 2 years after the diagnosis. CONCLUSIONS We presented a case of successful early chemotherapy for IVLBCL in an elderly patient with poor performance status. Early chemotherapy with CHOP, even before obtaining a definitive diagnosis based on immunostaining, may contribute to good outcomes.


Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/terapia , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Masculino
6.
Int J Hematol ; 109(4): 418-425, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30725360

RESUMO

Given the poor prognosis of patients with relapsed/refractory acute myeloid leukemia (AML), better therapy is needed. Fludarabine enhances the efficacy of Ara-C (cytarabine) by increasing intracellular Ara-C-triphosphate. The FLAG (fludarabine, high-dose Ara-C, supported with granulocyte colony-stimulating factor) regimen has been tested for use in AML patients by other investigators. In the phase II study reported here, we evaluated the efficacy and toxicity of FLAGM therapy (FLAG with mitoxantrone), further intensified by adding mitoxantrone, based on the results of a phase I study by our group. The major endpoints were complete remission (CR) rate and early death. From June 2004 to February 2008, 41 patients (median age 52 years; range 18-64 years) were enrolled. Thirty (73% 95% CI 58-84%) patients achieved CR, which met the primary endpoint; there was a single case of early death from pneumonia. Two-year overall survival was 39.4% (95% CI 25.2-55.6%). Of those who achieved CR, 27 underwent allogeneic stem cell transplantation (SCT), and 12 SCT recipients showed long-term survival. Grade 3/4 non-hematological adverse events included infection (59%), nausea/vomiting (15%), diarrhea (7%), and elevated liver enzymes (7%). In conclusion, FLAGM is an effective and safe salvage therapy for patients with relapsed/refractory AML, and facilitated SCT for a large proportion of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Recidiva , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados
7.
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
8.
Blood Adv ; 2(21): 2879-2889, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30381403

RESUMO

In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3-rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.


Assuntos
Ciclina D3/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Adolescente , Criança , Pré-Escolar , Ciclina D/genética , Ciclina D3/antagonistas & inibidores , Ciclina D3/metabolismo , Variações do Número de Cópias de DNA , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Rearranjo Gênico , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Mutação , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Recidiva , Taxa de Sobrevida
9.
Cancer Sci ; 109(10): 3235-3244, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30039554

RESUMO

Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.


Assuntos
Compostos de Anilina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacocinética , Creatina Quinase/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Japão/epidemiologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirazinas/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Receptor Tirosina Quinase Axl
10.
Support Care Cancer ; 26(12): 4187-4198, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29860713

RESUMO

PURPOSE: The Japan Adult Leukemia Study Group (JALSG) AML201 protocols are regimens for remission induction and consolidation chemotherapy of acute myeloid leukemia (AML) and have been widely accepted in Japan since 2001. Management of infectious complications during chemotherapy has a key role in the supportive care of AML patients. METHODS: By using case report forms collected in December 2001 and December 2005, we retrospectively analyzed the infectious complications in adult patients treated by using the JALSG AML201 protocols against AML (excluding promyelocytic leukemia). RESULTS: Of 980 patients, 80.2% experienced febrile neutropenia (FN), 8.3% bacteremia/fungemia, and 10.3% pulmonary infection at least once during remission-induction chemotherapy. Gram-positive bacteremia accounted for 65.1% of bacteremia/fungemia in 2001-2005, compared with 38.2% in 1987-1991 and 45.9% in 1992-1995. Of 750 patients, 81.9% experienced FN, 21.9% bacteremia/fungemia, and 9.1% pulmonary infection at least once during consolidation chemotherapy. During consolidation chemotherapy, bacteremia/fungemia and pulmonary infection were significantly more frequent in the high-dose cytarabine (HDAC) arm than in the conventional multiagent arm (25.9 vs. 17.9% and 12.7 vs. 7.7%, respectively). Invasive pulmonary aspergillosis accounted for 15.8% of pulmonary infections during remission induction and 19.7% during consolidation chemotherapy. CONCLUSIONS: Our data suggest that patterns of infectious complications have changed between 1987 and 2005, possibly because of chemoprophylaxis with oral fluoroquinolones and improved diagnosis of invasive pulmonary aspergillosis by serum antigen analysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bacteriemia/etiologia , Leucemia Mieloide Aguda/complicações , Bacteriemia/patologia , Feminino , História do Século XXI , Humanos , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Chest ; 153(5): e105-e112, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29731050

RESUMO

A 56-year-old woman presented to our hospital with a 4-month history of worsening chest pain. She denied having any respiratory symptoms, such as dyspnea, sputum, cough, or hemoptysis, or any history of smoking or exposure to dusts. One year previously she had a vertebral fracture. There was no specific family history, including pulmonary or autoimmune diseases. Chest CT performed 3 years earlier showed multiple thin-walled pulmonary cysts, although no further investigations were performed.


Assuntos
Dor no Peito/etiologia , Cistos/etiologia , Cadeias Leves de Imunoglobulina , Pneumopatias/diagnóstico , Mieloma Múltiplo/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade
12.
Leuk Res ; 66: 20-27, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29360622

RESUMO

Many genetic alterations that are associated with the prognosis of acute myeloid leukemia (AML) have been identified, and several risk stratification systems based on the genetic status have been recommended. The European LeukemiaNet (ELN) first proposed the risk stratification system for AML in 2010 (ELN-2010), and recently published the revised system (ELN-2017). We validated the long-term prognosis and clinical characteristics of each ELN-2017 risk category in Japanese adult AML patients who were treated in the Japan Adult Leukemia Study Group (JALSG) AML-201 study. We demonstrated that the 3-risk category system of the ELN-2017 successfully discriminated the overall survival and complete remission rates in our cohort in comparison with the 4-risk category of the ELN-2010. However, there were still genetic categories in which stratification of patients into favorable or intermediate risk categories was controversial; the low allelic ratio of FLT3-ITD was not necessarily associated with a better prognosis in patients with FLT3-ITD, and cytogenetic abnormalities may affect the prognosis in patients with favorable genetic lesions such as NPM1 and CEBPA mutations. As many molecular targeting agents, such as FLT3 inhibitors, have been developed, we must continue to modify the genetic risk stratification system to match the progression of therapeutic strategies.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT , Leucemia Mieloide Aguda , Proteínas Nucleares , Inibidores de Proteínas Quinases/administração & dosagem , Tirosina Quinase 3 Semelhante a fms , Adolescente , Adulto , Povo Asiático , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Medição de Risco , Taxa de Sobrevida , Fatores de Tempo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
13.
Ann Hematol ; 97(1): 73-81, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29196987

RESUMO

Recent studies have described various impacts of obesity and being overweight on acute myeloid leukemia (AML) outcomes in adult patients, but little is known about the impact of being underweight. We compared the outcomes of underweight patients to those of normal weight and overweight patients. Adult patients with AML who registered in the JALSG AML201 study (n = 1057) were classified into three groups: underweight (body mass index [BMI] < 18.5, n = 92), normal weight (BMI 18.5-25, n = 746), and overweight (BMI ≥ 25, n = 219). With the exception of age and male/female ratio, patient characteristics were comparable among the three groups. Rates of complete remission following induction chemotherapy were similar among the three groups (p = 0.68). We observed a significant difference in overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) between underweight and normal weight patients (3-year OS 34.8 vs. 47.7%, p = 0.01; DFS 28.6 vs. 39.8%, p = 0.02; 1-year NRM 6.2 vs. 2.6%, p = 0.05), but not between underweight and overweight patients. In multivariate analysis, underweight was an independent adverse prognostic factor for OS (p < 0.01), DFS (p = 0.01), and NRM (p = 0.04). During the first induction chemotherapy, the incidences of documented infection (DI) and severe adverse events (AEs) were higher in underweight patients than those in normal weight patients (DI 16 vs. 8.1%, p = 0.04; AE 36 vs. 24%, p = 0.05). In conclusion, underweight was an independent adverse prognostic factor for survival in adult AML patients.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Magreza/complicações , Magreza/mortalidade , Adolescente , Adulto , Índice de Massa Corporal , Peso Corporal/fisiologia , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
14.
Blood ; 131(2): 215-225, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29084771

RESUMO

Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.


Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/genética , Mutação , Cariótipo Anormal , Idoso , Epigênese Genética , Feminino , Dosagem de Genes , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , Prognóstico , Fator de Transcrição STAT3/genética
15.
Int J Hematol ; 107(2): 201-210, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29027108

RESUMO

Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years. FLT3-ITD (HR 2.10; 95% CI 1.07-4.12; p = 0.031) and NPM1 (HR 0.24; 95% CI 0.06-1.00; p = 0.050) mutations were associated with risk of overall mortality in multivariate analysis. OS was significantly different according to FLT3-ITD and NPM1 mutation status (p = 0.03). Survival was 100% with NPM1 mutations in the absence of FLT3-ITD and 35% (95% CI 14-57%) with FLT3-ITD in the absence of NPM1 mutations. The OS of AYAs, children (n = 413) and older adults (n = 124) of the AML-05 and AML201 participants were significantly different (p < 0.0001). This is the first report to combine clinical and genetic data of AYA AML from the major Japanese pediatric and adult study groups.


Assuntos
Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Humanos , Leucemia Mieloide Aguda/mortalidade , Análise Multivariada , Nucleofosmina , Prognóstico , Taxa de Sobrevida , Adulto Jovem
18.
Ther Drug Monit ; 39(3): 229-234, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28445212

RESUMO

BACKGROUND: The prophylactic administration of itraconazole (ITCZ) is effective for preventing mycotic infections during chemotherapy in patients with hematologic malignancies. However, fungal infections can occur when the ITCZ does not reach an effective concentration. METHODS: We conducted a prospective study to monitor the plasma concentration of ITCZ and hydroxyl-ITCZ (OH-ITCZ) weekly and to verify whether the day 3 plasma concentration of ITCZ could predict the subsequent acquisition of an effective plasma concentration. RESULTS: A total of 39 patients who underwent 66 courses of chemotherapy were assessed in this study. An effective plasma concentration was achieved on day 7 in 34 of 63 patients (54%) and on day 14 in 35 of 59 patients (59%). A univariate analysis revealed that age, type of chemotherapy, and the body surface area were significantly associated with a high plasma concentration of ITCZ + OH-ITCZ. A linear regression analysis extracted the body surface area and the type of chemotherapy as significant factors. An receiver operating characteristic curve analysis revealed a day 3 plasma ITCZ + OH-ITCZ concentration of >656 ng/mL led to a plasma concentration that exceeded the minimum effective level on day 7; the sensitivity and specificity were 62% and 93%, respectively. CONCLUSIONS: This study showed that the measurement of the day 3 plasma concentration could lead to a better outcome in patients receiving chemotherapy for hematologic malignancies.


Assuntos
Neoplasias Hematológicas/sangue , Itraconazol/sangue , Itraconazol/uso terapêutico , Micoses/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/sangue , Feminino , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/etiologia , Soluções Farmacêuticas/uso terapêutico , Estudos Prospectivos , Adulto Jovem
19.
Cancer Immunol Immunother ; 66(7): 851-863, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28321480

RESUMO

Wilms' tumor 1 (WT1) is a promising target of new immunotherapies for acute myeloid leukemia (AML) as well as for other cancers. OCV-501 is a helper peptide derived from the WT1 protein. OCV-501 induced OCV-501-specific Type 1 T-helper (Th1) responses dose-dependently and stimulated helper activity of the specific Th1 cells in peripheral blood mononuclear cells from healthy donors. OCV-501 also enhanced the increase in WT1-killer peptide-specific cytotoxic T lymphocytes. OCV-501 stimulated the OCV-501-specific Th1 clones in an HLA class-II restricted manner and formed a complex with HLA class-II protein. OCV-501-specific Th1 clones demonstrated significant OCV-501-specific cytolytic activity against OCV-501-pulsed B-lymphoblastoid cell line cells. Based on the pre-clinical results, phase 1 clinical trial was conducted. The result of this trial suggested that the subcutaneous administration of OCV-501 once weekly for 4 weeks at doses of 0.3, 1, and 3 mg in older patients with AML during complete remission was safe and well tolerated. The maximum tolerated dose was considered to be ≥3 mg. Of the nine subjects enrolled, neither relapse nor blast cells were observed during the study. Immunological responses were observed in OCV-501-specific delayed-type hypersensitivity test. This trial was registered at http://www.clinicaltrials.gov as NCT 01440920.


Assuntos
Vacinas Anticâncer/administração & dosagem , Leucemia Mieloide Aguda/terapia , Proteínas WT1/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Antígeno HLA-A2/genética , Cadeias beta de HLA-DR/genética , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Indução de Remissão , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacologia , Proteínas WT1/imunologia , Proteínas WT1/farmacologia
20.
Nat Genet ; 49(2): 204-212, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27992414

RESUMO

To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring.


Assuntos
Evolução Clonal/genética , Síndromes Mielodisplásicas/genética , Células Clonais/metabolismo , Progressão da Doença , Exoma/genética , Humanos , Leucemia Mieloide Aguda/genética , Mutação/genética , Nucleofosmina
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