RESUMEN
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.
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Janus Quinasa 2 , Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda , Receptores de Eritropoyetina , Exoma , Humanos , Janus Quinasa 2/genética , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación , Pronóstico , Receptores de Eritropoyetina/genéticaRESUMEN
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.
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Leucemia Mieloide Aguda , Proteínas WT1 , Anciano , Supervivencia sin Enfermedad , Humanos , Péptidos , Inducción de RemisiónRESUMEN
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.
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Leucemia Mieloide Aguda , Pirazinas , Compuestos de Anilina , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
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.
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Quistes , Neoplasias Pulmonares , Mieloma Múltiple , Quistes/cirugía , Femenino , Humanos , Pulmón , Neoplasias Pulmonares/diagnóstico , Persona de Mediana Edad , Cirugía Torácica Asistida por VideoAsunto(s)
Anomalía de Pelger-Huët/sangre , Anomalía de Pelger-Huët/diagnóstico , Adulto , Femenino , HumanosRESUMEN
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.
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Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/terapia , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/terapia , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , MasculinoRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Recurrencia , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
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.
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Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Represoras , Factores de Transcripción , Translocación Genética , Adolescente , Adulto , Anciano , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/biosíntesis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/biosíntesis , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/biosíntesis , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Tasa de Supervivencia , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
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.
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Ciclina D3/genética , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/patología , Proteína de la Leucemia Mieloide-Linfoide/genética , Adolescente , Niño , Preescolar , Ciclina D/genética , Ciclina D3/antagonistas & inhibidores , Ciclina D3/metabolismo , Variaciones en el Número de Copia de ADN , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Reordenamiento Génico , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Recurrencia , Tasa de SupervivenciaRESUMEN
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.
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Compuestos de Anilina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/farmacocinética , Creatina Quinasa/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Japón/epidemiología , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirazinas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa del Receptor AxlRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bacteriemia/etiología , Leucemia Mieloide Aguda/complicaciones , Bacteriemia/patología , Femenino , Historia del Siglo XXI , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
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.
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Dolor en el Pecho/etiología , Quistes/etiología , Cadenas Ligeras de Inmunoglobulina , Enfermedades Pulmonares/diagnóstico , Mieloma Múltiple/diagnóstico , Femenino , Humanos , Persona de Mediana EdadRESUMEN
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.
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Proteínas Potenciadoras de Unión a CCAAT , Leucemia Mieloide Aguda , Proteínas Nucleares , Inhibidores de Proteínas Quinasas/administración & dosificación , Tirosina Quinasa 3 Similar a fms , Adolescente , Adulto , Pueblo Asiatico , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Medición de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
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.
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Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Delgadez/complicaciones , Delgadez/mortalidad , Adolescente , Adulto , Índice de Masa Corporal , Peso Corporal/fisiología , Femenino , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
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.
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Leucemia Mieloide Aguda/genética , Mutación , Proteínas Nucleares/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Humanos , Leucemia Mieloide Aguda/mortalidad , Análisis Multivariante , Nucleofosmina , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
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.
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Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/genética , Mutación , Cariotipo Anormal , Anciano , Epigénesis Genética , Femenino , Dosificación de Gen , Humanos , Factores Reguladores del Interferón/genética , Masculino , Persona de Mediana Edad , Modelos Moleculares , Polimorfismo de Nucleótido Simple , Pronóstico , Factor de Transcripción STAT3/genéticaAsunto(s)
Leucemia Mieloide Aguda , Guías de Práctica Clínica como Asunto , Factores de Edad , Anciano , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/administración & dosificación , Citarabina/análogos & derivados , Daunorrubicina/administración & dosificación , Femenino , Terapia Genética , Hematología/organización & administración , Trasplante de Células Madre Hematopoyéticas , Humanos , Quimioterapia de Inducción , Japón , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Sociedades Médicas/organización & administraciónAsunto(s)
Duramadre/diagnóstico por imagen , Duramadre/patología , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Mieloma Múltiple/diagnóstico por imagen , Neoplasias Primarias Múltiples , Neoplasias Craneales/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Cadenas lambda de Inmunoglobulina , Persona de Mediana Edad , Mieloma Múltiple/patología , Invasividad Neoplásica , Neoplasias Craneales/patología , Sindecano-1RESUMEN
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.
Asunto(s)
Neoplasias Hematológicas/sangre , Itraconazol/sangre , Itraconazol/uso terapéutico , Micosis/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antifúngicos/sangre , Femenino , Neoplasias Hematológicas/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Micosis/etiología , Soluciones Farmacéuticas/uso terapéutico , Estudios Prospectivos , Adulto JovenRESUMEN
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.