RESUMO
An emerging group of spindle cell neoplasms harboring fusions involving NTRK or non-NTRK kinase genes often share characteristic S100 and/or CD34 expression; however, the diagnostic utility of immunohistochemical stains is not well established in this family owing to their lack of specificity. Recently, CD30 expression in spindle cell neoplasms with kinase gene fusions, such as NTRK, BRAF, RAF1, and RET, has been increasingly identified. We herein report a 10-year-old girl with high-grade spindle cell sarcoma of the neck. Prior to histopathological evaluation, flow cytometry (FCM) analysis and touch smear cytology of the tumor tissue revealed CD34+ and dimCD30+ spindle cell populations. Histopathologically, the case was characterized by monomorphic spindle-shaped cytomorphology with CD30, S100, and CD34 positivity and harbored close similarities with spindle cell neoplasms with NTRK or non-NTRK gene fusions. Subsequently, a comprehensive next-generation sequencing sarcoma panel identified a rare PLEKHH2::ALK fusion, and a diagnosis of ALK-rearranged spindle cell neoplasm was made. The patient showed significant tumor response to single-agent treatment with alectinib, an ALK-tyrosine kinase inhibitor. This case supports that CD30 is expressed in an ALK-rearranged mesenchymal neoplasm. The benefit of the early detection of CD30 expression by FCM for a prompt diagnosis and treatment is highlighted in the context of an aggressive clinical course. This case represents a learning experience regarding the need to the check the status of CD30 expression in these tumors and suggests the potential clinical benefits of CD30-targeted therapy.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Criança , Imuno-Histoquímica , Citometria de Fluxo , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fusão Gênica , Receptores Proteína Tirosina Quinases/genética , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.
Assuntos
Linfoma de Burkitt , Leucemia , Linfoma Difuso de Grandes Células B , Humanos , Criança , Rituximab/efeitos adversos , Linfoma de Burkitt/tratamento farmacológico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Intervalo Livre de Progressão , Leucemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is classified into two molecular subtypes according to its cell of origin: germinal center B-cell (GCB) subtype and activated B-cell/non-GCB subtype. This latter subtype shows a poorer prognosis in adults. However, in pediatric DLBCL, the prognostic impact of the subtype is yet to be clarified. OBJECTIVES: This study sought to compare the prognosis between GCB and non-GCB DLBCL in a large number of cases in children and adolescents. In addition, this study intended to describe the clinical, immunohistochemical, and cytogenetic characteristics of these two molecular subtypes of DLBCL, and consider differences in the biology, frequency, and prognosis of GCB and non-GCB subtypes in pediatric versus adult DLBCL or in Japanese versus Western pediatric DLBCL patients. DESIGN/METHODS: We selected mature B-cell lymphoma/leukemia patients for whom specimens had been submitted to the central pathology review in Japan between June 2005 and November 2019. We referred the past studies on Asian adult patients and Western pediatric patients to compare with our results. RESULTS: Data were obtained from 199 DLBCL patients. The median age of all patients was 10 years, with 125 patients (62.8%) in the GCB group and 49 (24.6%) in the non-GCB group other than 25 cases whose immunohistochemical data were insufficient. Overall, the percentage of translocation of MYC (1.4%) and BCL6 (6.3%) was lower than in adult and Western pediatric DLBCL cases. The non-GCB group showed a significantly higher proportion of females (44.9%), a higher incidence of stage III disease (38.8%), and B-cell lymphoma 2 (BCL2)-positivity in immunohistochemistry (79.6%) compared to the GCB group; however, no BCL2 rearrangement was observed in both GCB and non-GCB groups. The prognosis did not differ significantly between the GCB and non-GCB groups. CONCLUSION: This study including a large number of non-GCB patients showed the same prognosis between GCB and non-GCB groups and suggested a difference in the biology of pediatric and adolescent DLBCL compared to adult DLBCL as well as between Asian and Western DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B , Adulto , Feminino , Adolescente , Humanos , Criança , Estudos Retrospectivos , Japão/epidemiologia , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/patologia , Linfócitos B , PrognósticoRESUMO
In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Osteonecrose/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Feminino , Humanos , Incidência , Lactente , Japão/epidemiologia , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Retrospectivos , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
6-Mercaptopurine (6-MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP-associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6-MP, using sandwich enzyme-linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.
Assuntos
Mercaptopurina , Pirofosfatases , Criança , Humanos , Anticorpos Monoclonais/uso terapêutico , Mercaptopurina/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatases/genética , Tioguanina/uso terapêuticoRESUMO
Peripheral T-cell lymphoma (PTCL) is a group of heterogeneous non-Hodgkin lymphomas showing a mature T-cell or natural killer cell phenotype, but its molecular abnormalities in paediatric patients remain unclear. By employing next-generation sequencing and multiplex ligation-dependent probe amplification of tumour samples from 26 patients, we identified somatic alterations in paediatric PTCL including Epstein-Barr virus (EBV)-negative (EBV- ) and EBV-positive (EBV+ ) patients. As recurrent mutational targets for PTCL, we identified several previously unreported genes, including TNS1, ZFHX3, LRP2, NCOA2 and HOXA1, as well as genes previously reported in adult patients, e.g. TET2, CDKN2A, STAT3 and TP53. However, for other reported mutations, VAV1-related abnormalities were absent and mutations of NRAS, GATA3 and JAK3 showed a low frequency in our cohort. Concerning the association of EBV infection, two novel fusion genes: STAG2-AFF2 and ITPR2-FSTL4, and deletion and alteration of CDKN2A/2B, LMO1 and HOXA1 were identified in EBV- PTCL, but not in EBV+ PTCL. Conversely, alterations of PCDHGA4, ADAR, CUL9 and TP53 were identified only in EBV+ PTCL. Our observations suggest a clear difference in the molecular mechanism of onset between paediatric and adult PTCL and a difference in the characteristics of genetic alterations between EBV- and EBV+ paediatric PTCL.
Assuntos
Linfoma de Células T Periférico/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Japão/epidemiologia , Linfoma de Células T Periférico/epidemiologia , Masculino , Sequenciamento do ExomaRESUMO
Anaplastic lymphoma kinase (ALK) inhibition is expected to be a promising therapeutic strategy for ALK-positive malignancies. We aimed to examine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL). This open-label, phase II trial included patients (aged 6 years or older) with relapsed or refractory ALK-positive ALCL. Alectinib 300 mg was given orally twice a day (600 mg/d) for 16 cycles, and the duration of each cycle was 21 days. Patients who weighed less than 35 kg were given a reduced dose of alectinib of 150 mg twice a day (300 mg/d). Ten patients were enrolled, and the median age was 19.5 years (range, 6-70 years). Objective responses were documented in eight of 10 patients (80%; 90% confidence interval, 56.2-95.9), with six complete responses. The 1-year progression-free survival, event-free survival, and overall survival rates were 58.3%, 70.0%, and 70.0%, respectively. The median duration of therapy was 340 days. No unexpected adverse events occurred. The most common grade 3 and higher adverse event was a decrease in neutrophil count in two patients. Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who had progressed on standard chemotherapy. Based on the results of the current study, the Ministry of Health, Labour and Welfare of Japan approved alectinib for the treatment of recurrent or refractory ALK-positive ALCL in February 2020.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/administração & dosagem , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Adulto , Idoso , Quinase do Linfoma Anaplásico/sangue , Carbazóis/efeitos adversos , Carbazóis/farmacocinética , Criança , Intervalos de Confiança , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Japão , Linfoma Anaplásico de Células Grandes/mortalidade , Masculino , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Recidiva , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
No standard treatment for relapsed or refractory anaplastic large-cell lymphoma (ALCL) has been established. This study is a multicenter, open-label trial to examine the effectiveness and safety of transplantation with reduced-intensity conditioning (RIC) for patients under 20 years old with relapsed or refractory ALCL. We defined RIC as the administration of fludarabine (30 mg/m2/day) for five days plus melphalan (70 mg/m2/day) for two days and total body irradiation at 4 Gy, followed by allogeneic hematopoietic stem cell transplantation.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Anaplásico de Células Grandes/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Ensaios Clínicos como Assunto , Humanos , Melfalan/uso terapêutico , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoAssuntos
Linfoma Anaplásico de Células Grandes , Linfoma , Criança , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Prognóstico , Receptores Proteína Tirosina Quinases/genética , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) are the two most common tumors expressing CD30. Internationally, a clinical study that is being conducted involving adults with recurrent or refractory HL or ALCL suggests efficacy of brentuximab vedotin (SGN-35). Pediatric patients should be given medicines that have been appropriately evaluated for their use. In the past, however, new approved drugs have been used for pediatric patients without the confirmation of safety and efficacy in pediatric patients. Therefore, it is important to examine the safety and efficacy of SGN-35 in Japanese children. METHODS: Phase I clinical study of SGN-35 involving children with recurrent or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma (BV-HLALCL study) is being conducted for pediatric patients in order to evaluate the safety, feasibility and preliminary clinical effectiveness of brentuximab vedotin. SGN-35 is intravenously administered on Day 1 of each cycle (21 days/cycle). The dose of SGN-35 is calculated based on the body weight at the baseline. The primary endpoint is dose limiting toxicity and incidence of adverse events. The secondary endpoints are pharmacokinetics, response rate, complete remission rate, response duration, progression-free survival and event-free survival. The reduction rate of tumor will be calculated according to revised response criteria for malignant lymphoma for measurable tumor. Six pediatric patients will be enrolled in this study. DISCUSSION: This study aims to expand indication of SGN-35 in Japan by assessing its safety and efficacy in pediatric patients. TRIAL REGISTRATION: JMACCT ID: JMA-IIA00229 . Registered on 17 Nov 2015.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/administração & dosagem , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Adolescente , Brentuximab Vedotin , Criança , Pré-Escolar , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/efeitos adversos , Japão , Antígeno Ki-1/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Recidiva Local de Neoplasia , Indução de RemissãoRESUMO
BACKGROUND: Currently, there is no standardized treatment for adolescents, aged 15 years or older, with mature B-cell non-Hodgkin lymphoma (B-NHL), although this age group has been reported to have a poorer prognosis than younger patients. PROCEDURE: The present study analyzed the data of 321 patients with B-NHL, enrolled in a pediatric clinical trial, comparing the treatment outcomes between adolescents (aged 15-18 years, n = 25) and children (≤15 years, n = 297), with a particular focus on the safety and tolerability of administering pediatric regimens to adolescents. RESULTS: The probability of event-free survival (EFS) at 4 years was 79.3 ± 8.3% for the adolescents and 88.0 ± 1.9% for the children (P = 0.236). After adjusting for treatment group and lactate dehydrogenase value at the time of diagnosis, the probability of 4-year EFS of adolescents was lower than that of children, but only in the patients with central nervous system positive lymphoma or Burkitt leukemia. The frequency of treatment-related mortalities, severe adverse events (SAEs), and SAEs leading to treatment discontinuation or treatment completion rate was similar in adolescent and pediatric patients. There was no difference in treatment duration between adolescent and pediatric patients. CONCLUSIONS: The treatment outcomes of adolescents with B-NHL were not statistically different from those of the pediatric patients and the safety of a pediatric regimen in adolescents was similar to that in the pediatric patients. A pediatric treatment foundation can be adopted for adolescents, although further prospective studies and biological investigations are required for treatment optimization.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/mortalidade , Masculino , Resultado do TratamentoRESUMO
We reviewed the immunophenotypic subtypes of pediatric T-cell lymphoblastic lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 study. Of the 104 patients, 40 patients each had sufficient data to evaluate the immunophenotypes and early T-cell precursor (ETP) subtype. Pro-T, pre-T, intermediate T, and mature T cells were observed in 1, 9, 21, and 9 cases, respectively. The 3-year event-free survival (EFS) rates of those with pro-T/pre-T, intermediate T, and mature T cells were 80.0±12.6%, 71.4±9.9%, and 88.9±10.5%, respectively (P=0.546). There were 8 and 32 cases of ETP and non-ETP subtypes, with 3-year EFS rates of 75.0±15.3% and 71.9±8.0%, respectively (P=0.828), indicating that the immunophenotypic subtype was not predictive of EFS in this study.
Assuntos
Células Precursoras de Linfócitos T/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Prognóstico , Criança , Feminino , Humanos , Imunofenotipagem , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Estudos Retrospectivos , Análise de Sobrevida , Subpopulações de Linfócitos T/patologiaRESUMO
Pediatric patients with lymphoblastic lymphoma are generally treated using the Berlin-Frankfurt-Munster (BFM) 90 protocol, which is the standard treatment strategy for pediatric acute lymphoblastic leukemia, and have a favorable outcome. However, this intense regimen includes high total doses of anthracycline and alkylating agents, and is known to cause late complications. We therefore planned a clinical trial to examine the efficacy and safety of a modified BFM regimen. We expect that this phase II, nationwide multicenter trial will help to establish an effective and safer standard therapy for stage I/II pediatric lymphoblastic lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Asparaginase , Criança , Ciclofosfamida , Citarabina , Dexametasona , Doxorrubicina , Humanos , Estudos Multicêntricos como Assunto , Tioguanina , VincristinaRESUMO
Crizotinib is an inhibitor of multiple tyrosine kinases, including the anaplastic lymphoma kinase (ALK). Responses to crizotinib have also been reported in patients with ALK-positive anaplastic large-cell lymphoma (ALCL) and solid tumors with ALK-mutation, including neuroblastoma. Optimal treatment for patients with recurrent or refractory ALK-positive ALCL and neuroblastoma has not been established. There is a need to develop new drugs for these patients. The objectives of this trial are to evaluate the tolerability and safety of crizotinib in Japanese patients with recurrent/refractory ALK-positive ALCL or neuroblastoma (phase I) and its efficacy in recurrent/refractory ALK-positive ALCL (phase II).
Assuntos
Quinase do Linfoma Anaplásico/análise , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Crizotinibe/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Criança , Pré-Escolar , Crizotinibe/efeitos adversos , Humanos , Lactente , Linfoma Anaplásico de Células Grandes/enzimologia , Estudos Multicêntricos como Assunto , RecidivaRESUMO
This trial enrolls patients with untreated Hodgkin's lymphoma aged<20 years at diagnosis and examines the effects of omitting radiation therapy if the FDG-positron emission tomography (PET) findings after two completed cycles of combination chemotherapy are negative. It thereby aims to determine whether patients who truly require radiation therapy can be identified by FDG-PET. If so, this modality could be used to omit radiation therapy for all other patients, decreasing the risk of serious long-term complications without affecting survival rates. The outcomes of patients for whom FDG-PET is used to assess early treatment response will also be determined.
Assuntos
Ensaios Clínicos Fase II como Assunto , Fluordesoxiglucose F18 , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Criança , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/mortalidade , Humanos , Masculino , Estudos Multicêntricos como Assunto , Estudos RetrospectivosRESUMO
Hematological malignancies (HM) comprise the major proportion of the cancer incidence and mortality in the adolescent and young adult (AYA) age group. Even though age-related differences in tumor biology have been reported in HM, further biological studies are warranted for elucidating age-related differences in AYAs. Hemato-oncologists and pediatric oncologists frequently follow various treatment strategies for HM, as the treatment strategy that is more suitable for this age group remains unclear. Recently, the involvement of pediatric oncologists has increased because the advantage of pediatric-type treatment has been demonstrated in acute lymphoblastic leukemia (ALL) and the significance of long-term follow-up has been clarified. However, for HM, except for ALL, the pediatric- and adult-type therapy that is more suitable for AYAs remains unclear. This review aimed to describe the challenges in the context of major HM affecting the AYA age group (acute leukemia and lymphoma). For assessing the outcome of AYAs with HM, we need to consider not only the treatment strategy but also other factors such as differences in aging and tumor biology. Furthermore, it is imperative to develop a therapy that resolves psychosocial problems peculiar to AYAs.
Assuntos
Neoplasias Hematológicas/terapia , Adolescente , Humanos , Leucemia Mieloide Aguda , Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto JovemRESUMO
Currently, a standard therapy has not been established for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. While there are many treatment options, such as hematopoietic stem cell transplantation, patients with resistant disease to conventional chemotherapies have particularly poor prognosis. There is urgent need to develop new drugs because of the lack of a standard therapy and poor prognoses. This phase II trial is designed for evaluating the efficacy and safety of alectinib hydrochloride for patients with recurrent or refractory anaplastic lymphoma kinase -positive anaplastic large cell lymphoma. The primary endpoint is the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints are pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events. The results of this trial will be the pivotal data for the drug approval of alectinib hydrochloride for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.
Assuntos
Carbazóis/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/metabolismo , Masculino , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
Since adolescents and young adults (AYAs) with lymphoma began to be treated by pediatric hematologists and hematology physicians, few data have been collected regarding lymphoma in this generation of patients in Japan. We analyzed the number of pediatric hospitals that have treated hematological AYA patients. In half of the pediatric facilities, patients >15 years of age had been treated, and 40% of those facilities treated >1 AYA every year. A past lymphoma study by the Japanese Pediatric Leukemia/Lymphoma Study Group included some AYA patients. However, only the B-NHL03 study analyzed the difference between children and AYAs. In that study, 25 AYAs (7.8%) were treated among all 321 study patients. The 5-year overall survival rates of patients aged <10, 10-14, >14 years, were 88.7%, 87.0%, and 79.3%, respectively. However, this difference was not statistically significant because of the less number of patients. We analyzed data of stem cell transplantation in patients with non-Hodgkin lymphoma (NHL). Of the allogeneic transplant patients, children and AYAs did not significantly differ in treatment results. However, the 5-year transplant-related mortality after autologous transplantation was significantly higher in children than in AYAs. In NHL patients, the survival rate of AYAs after transplantation was not inferior to that of children.
Assuntos
Linfoma , Adolescente , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma/terapia , Adulto JovemRESUMO
BACKGROUND: Childhood advanced lymphoblastic lymphoma (LBL) has a favorable outcome with an event-free survival (EFS) rate of over 80% in response to treatment strategies for acute lymphoblastic leukemia (ALL). However, no progress has been made in this outcome over the past 10 years. PROCEDURE: We conducted the first nationwide prospective study of childhood advanced LBL to assess the efficacy and safety of ALL-directed therapy with an intensified maintenance phase. We omitted local radiotherapy including prophylactic cranial radiotherapy except for patients with initial central nervous system disease. The total duration of the treatment was 24 months. RESULTS: For the 136 patients analyzed in this study, 5-year overall survival (OS) was 82.9% and 5-year EFS was 77.9%. Thirty events were observed and 14 occurred before the initiation of intensified maintenance phase. Of 14 events, nine were observed as mediastinal enlargement. There was no significant difference in outcome when stratified according to gender or by immunophenotype. The 5-year EFS according to clinical stage in patients with T-cell LBL (T-LBL) was 70.6% for stage III and 88.9% for stage IV (P = 0.037). CONCLUSIONS: Our first nationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve the survival outcome. There was a trend of better EFS in Japanese patients with T-LBL stage IV than T-LBL stage III.
Assuntos
Quimioterapia de Manutenção/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Estudos Prospectivos , Falha de Tratamento , Resultado do TratamentoRESUMO
Cure rates for pediatric hematologic malignancies (HM) have improved dramatically due to the intensive use of conventional chemotherapy and hematopoietic stem cell transplantation. However, many children still die of their disease or treatment-related toxicities. Even in patients experiencing an apparent cure, there can be significant acute and late complications of treatment. Further improvements of therapy will likely depend on the development of new therapeutic strategies. Immune-based therapy, for example monoclonal antibody-based and adoptive T-cell therapies, offers an attractive alternative that has emerged as a potent treatment strategy. Drug repositioning of molecular target drugs is now receiving remarkable attention, especially that based on recent genome wide studies. However, there are many obstacles to overcome in developing these novel drugs for pediatric patients. Pediatric drug development is difficult in itself because many of these agents are not profitable, largely due to their being too few patients, preclinical models are limited, there are too few formulations for children, special ethical considerations must be addressed when treating children and so on. Obstacles to the development of new drugs are a characteristic feature of pediatric HM. Furthermore, the approach to developing drugs for pharmaceutical approval is quite different from that to developing new therapies using approved drugs and is not well-known among investigators. Although many challenges remain in pediatric hematologic anticancer drug development, none are insurmountable.