RESUMO
Between 2007 and 2013, 13 children diagnosed with primary mediastinal large B-cell lymphoma (PMLBL) were treated according to a modified version of AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) LNH-97 protocol based on high-dose methotrexate, anthracyclines, and addition of anti-CD20. Ten patients achieved a continuous complete remission with front-line therapy. The overall 5-year survival was 91.7%, and event-free survival was 83.9%, with only one patient dying of progressive disease. Despite the few cases, these results demonstrate that this therapy, which includes anti-CD20, given in a multicenter setting, is feasible with acceptable toxicity in children with PMLBL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/metabolismo , Adolescente , Criança , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Estudos Retrospectivos , Rituximab/administração & dosagem , Taxa de SobrevidaRESUMO
Drug-related toxicities represent an important clinical concern in chemotherapy, genetic variants could help tailoring treatment to patient. A pharmacogenetic multicentric study was performed on 508 pediatric acute lymphoblastic leukemia patients treated with AIEOP-BFM 2000 protocol: 28 variants were genotyped by VeraCode and Taqman technologies, deletions of GST-M1 and GST-T1 by multiplex PCR. Toxicities were derived from a central database: 251 patients (49.4%) experienced at least one gastrointestinal (GI) or hepatic (HEP) or neurological (NEU) grade III/IV episode during the remission induction phase: GI occurred in 63 patients (12.4%); HEP in 204 (40.2%) and NEU in 44 (8.7%). Logistic regression model adjusted for sex, risk and treatment phase revealed that ITPA rs1127354 homozygous mutated patients showed an increased risk of severe GI and NEU. ABCC1 rs246240 and ADORA2A rs2236624 homozygous mutated genotypes were associated to NEU and HEP, respectively. These three variants could be putative predictive markers for chemotherapy-related toxicities in AIEOP-BFM protocols.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Gastroenteropatias/genética , Doenças do Sistema Nervoso/genética , Farmacogenética/métodos , Variantes Farmacogenômicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Quimioterapia de Consolidação/efeitos adversos , Feminino , Gastroenteropatias/induzido quimicamente , Deleção de Genes , Predisposição Genética para Doença , Glutationa Transferase/genética , Humanos , Quimioterapia de Indução/efeitos adversos , Lactente , Modelos Logísticos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Reação em Cadeia da Polimerase Multiplex , Mutação , Doenças do Sistema Nervoso/induzido quimicamente , Testes Farmacogenômicos/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Valor Preditivo dos Testes , Pirofosfatases/genética , Receptor A2A de Adenosina/genética , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Five Asociación de Hemato-Oncología de Centroamérica (AHOPCA) countries have used an adapted BFM-based protocol for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: In the AHOPCA-ALL 2008 protocol, patients were stratified by age, white blood cell count, immunophenotype, central nervous system involvement, day 8 prednisone response, and morphologic bone marrow response to induction therapy. Patients at Standard Risk (SR) received a three-drug induction regimen, a reinduction phase, and maintenance with protracted intrathecal therapy. Those at Intermediate (IR) and High Risk (HR) received, in addition, daunorubicin during induction therapy, a consolidation phase and two or three reinduction phases respectively. RESULTS: From August 2008 through July 2012, 1,313 patients were enrolled: 353 in SR, 548 in IR, 412 in HR. During induction therapy, 3.0% of patients died, 2.7% abandoned treatment, 1.1% had resistant ALL, and 93.2% achieved morphological complete remission (CR). Deaths and abandonment in first CR occurred in 2.7% and in 7.0% of patients, respectively. The relapse rate at a median observation time of 2.1 years was 15.0%. At 3 years, the event-free survival (EFS) and overall survival (OS), with abandonment considered as an event, were 59.4% (SE 1.7) and 68.2% (SE 1.6). Three-year EFS was 68.5% (SE 3.0), 62.1% (SE 2.6), and 47.8% (SE 3.2) for SR, IR, and HR groups. Adolescents had a significantly higher relapse rate (P = 0.001). CONCLUSIONS: This experience shows that common international studies are feasible in lower-middle income countries. Toxic deaths, abandonment of treatment, and relapses remain major obstacles to the successful treatment. Alternative treatment strategies may be beneficial.
Assuntos
Países em Desenvolvimento , Recidiva Local de Neoplasia/terapia , Segunda Neoplasia Primária/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , América Central , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Imunofenotipagem , Renda , Lactente , Recém-Nascido , Masculino , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/mortalidade , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/mortalidade , Pobreza , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Suspensão de Tratamento/economiaRESUMO
BACKGROUND: The role of FDG-PET in Wilms' tumor has not been well established. The aim of this report is to describe the role of FDG-PET to assess chemotherapy efficacy and to show potential correlations between different Standardized Uptake Values (SUVs) and histopathological features in a patient with persisting metastatic disease. CASE DESCRIPTION: A 3-year-old boy was diagnosed with Wilms' tumor without anaplasia. The patient underwent treatment as according to the AIEOP-TW-2003 protocol, for stage III tumors. Therapy was discontinued with no evidence of disease, yet 9 months later thorax metastases were found. Although second and third line treatments were administered, conventional imaging demonstrated stable disease. Metronomic chemotherapy as well was employed for 44 months and FDG-PET was annually performed basing on responsible local physician choice trying to better describe the disease status. Four months after fourth line treatment was stopped, the patient manifested clinical symptoms; lesions began to increase their metabolic activity inhomogeneously. Therapy was hence restarted and SUVs decreased. Metastasectomies were then performed and histology revealed a correlation between viable disease shown by higher FDG-PET uptake and viable tumor areas. CONCLUSIONS: Our case discussion demonstrates that FDG-PET is potentially valuable in Wilms' tumor correlating SUV values and histological features of the tumor after chemotherapy. This case suggests that FDG-PET is a valid tool to assess chemotherapy response in relapsed Wilms' tumor even in case of no evidence of significant dimensional changes under conventional imaging.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fluordesoxiglucose F18/administração & dosagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Tumor de Wilms , Pré-Escolar , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Radiografia , Fatores de Tempo , Tumor de Wilms/diagnóstico por imagem , Tumor de Wilms/prevenção & controleRESUMO
We report the results of a protocol for the diagnosis and treatment of pediatric non-Hodgkin lymphomas (NHL) conducted in Nicaragua in the context of an international collaborative program. Fifty-three children with NHL treated between 1996 and 2003 were retrospectively evaluated. Therapy was designed based on local drug availability and affordability with dose and schedule adaptations for Burkitt and lymphoblastic lymphomas. With a median follow-up of 3 years, the projected 9-year overall survival was 63% and event-free survival 53%. The treatment was efficacious, feasible, and well tolerated in spite of the local socio-economical conditions.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Países em Desenvolvimento , Linfoma não Hodgkin/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , NicaráguaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/história , Quimioterapia de Indução/história , Quimioterapia de Indução/métodos , Oncologia/história , Pediatria/história , Leucemia-Linfoma Linfoblástico de Células Precursoras/história , Asparaginase/história , Criança , Ciclofosfamida/história , Citarabina/história , Dexametasona/história , Doxorrubicina/história , Alemanha , História do Século XX , História do Século XXI , Humanos , Tioguanina/história , Vincristina/históriaRESUMO
Between 1995 and 2004, six International Childhood Acute Lymphoblastic Leukemia (ALL) Workshop have been held, and the completion of several collaborative projects has established the clinical relevance and treatment options for several specific genetic subtypes of ALL. This meeting report summarizes the data presented in the seventh meeting and the discussion.
Assuntos
Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antineoplásicos/uso terapêutico , Criança , Coleta de Dados , Humanos , Itália , Fatores de RiscoRESUMO
Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
Assuntos
Deleção de Genes , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/análise , Humanos , Lactente , Cooperação Internacional , Proteínas de Fusão Oncogênica/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: The microgranular variant (M3v) of acute promyelocytic leukemia (APL) rarely has been reported in a pediatric series of acute nonlymphoblastic leukemia (AnLL). We reviewed the clinical and biologic features of childhood M3v cases in our AnLL series. PATIENTS AND METHODS: From January 1970 to January 1991, 11 children with M3v were admitted and treated at our center. A diagnosis was made according to French-American-British (FAB) criteria. Morphologic examination, cytochemical analysis, and immunophenotyping were performed by a single pathologist. From January 1984, the diagnosis was confirmed by cytogenetic and, subsequently, by molecular analysis on frozen material. RESULTS: In our series, the overall incidence of children with APL was unusually high, 31.2% of the AnLL and M3v constituted one case in every four cases of APL. Even restriction of the analysis to the time when either cytogenetic and DNA studies confirmed the diagnosis, the incidence did not change. The immunophenotype of M3v cases was identical to that described for the hypergranular type, but an unexpected association of CD2 with M3v was shown. The onset was characterized by marked hyperleukocytosis (median WBC count, 87 x 10(9)/L) unlike classic APL. Disseminated intravascular coagulation (DIC) was always present and severe. Hyperleukocytosis and DIC were responsible for the high incidence of deaths for hemorrhagic events in the first days after onset (eight of 11 patients). CONCLUSIONS: In our experience, for unknown reasons, M3v may occur in childhood more than generally was considered. The clinical course and prognosis seem worse in M3v than in typical APL cases.
Assuntos
Leucemia Promielocítica Aguda/patologia , Adolescente , Criança , Pré-Escolar , DNA de Neoplasias/análise , Feminino , Humanos , Imunofenotipagem , Incidência , Lactente , Leucemia Promielocítica Aguda/genética , Masculino , PrognósticoRESUMO
PURPOSE: To assess in a randomized study the therapeutic effect of the addition of high-dose L-asparaginase (HD ASP) in the context of a Berlin-Frankfurt-Münster (BFM)-based chemotherapy regimen for intermediate risk (IR) childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From March 1991 to April 1995, a total of 705 patients, with 59% of the cohort of patients fewer than 15 years old, with newly diagnosed non-B ALL, enrolled onto the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study, were assigned to the IR group. Patients in remission at the beginning of the reinduction phase were randomized either to the standard treatment (SD ASP arm) or the experimental treatment (HD ASP arm; weekly intramuscular administration of HD ASP 25,000 IU/m(2) repeated for a total of 20 weeks). Most of the patients (90%) were treated with Erwinia chrysanthemi L-asparaginase product. RESULTS: Among the 610 patients randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288), relapse occurred at a median time of 24 months after randomization in 76 (24%) and in 64 children (22%), respectively. Most of the relapses occurred in the marrow (100 isolated, 21 combined). There was no significant difference between the disease-free survival in the two treatment arms (P =.64), with estimated values at 7 years from randomization of 72.4% (SE 3.1) v 75.7% (SE 2.6) in the SD ASP and HD ASP arms, respectively. CONCLUSION: No advantage was observed for IR ALL children treated with BFM-based intensive chemotherapy who received protracted E chrysanthemi HD ASP during reinduction and the early continuation phase.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Asparaginase/farmacologia , Asparaginase/uso terapêutico , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Injeções Intramusculares , Masculino , Resultado do TratamentoRESUMO
PURPOSE: To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy. PATIENTS: Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients. RESULTS: Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group. CONCLUSION: Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/prevenção & controle , Irradiação Craniana , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Adolescente , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Humanos , Lactente , Injeções Espinhais , Masculino , Mercaptopurina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Recidiva , Análise de Regressão , Indução de Remissão , Análise de Sobrevida , Vincristina/administração & dosagemRESUMO
PURPOSE: The ALL-BFM 90 and AIEOP-ALL 91 studies share the same treatment backbone and have 5-year event-free survival (EFS) rates close to 75%. This study evaluated the impact of differing presymptomatic CNS therapies in T-cell acute lymphoblastic leukemia (T-ALL) patients with a good response to prednisone (PGR) according to WBC count and Berlin-Frankfurt-Münster (BFM) risk factor (RF). PATIENTS: A total of 192 patients (141 boys; median age, 7.5 years) with T-ALL, PGR, RF less than 1.7, and no CNS leukemia diagnosed between 1990 and 1995 were enrolled onto the ALL-BFM 90 (n = 123) or AIEOP-ALL 91 (n = 69) study. Presymptomatic CNS therapy consisted of cranial radiation (CRT) and intrathecal methotrexate (I.T. MTX) (11 doses) in the BFM study and of extended triple intrathecal therapy (T.I.T.) (17 doses) in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study. Patients were divided into a low-WBC group (WBC count < 100,000/microL) and a high-WBC group (WBC count > 100,000/microL). EFS was compared using the log-rank test. RESULTS: For patients treated with CRT and I.T. MTX (BFM group), the 3-year EFS rate was 89.8% (SE = 3.5) for 99 patients in the low-WBC group versus 81.9% (SE = 8.2) in the high-WBC group (difference not significant). Conversely, for patients treated with T.I.T. alone (AIEOP group), the EFS rate was 80.6% (SE = 5.6) in 55 patients with a low WBC count versus 17.9% (SE = 11.0) in 14 patients with a high WBC count (P < .001). CONCLUSION: These data suggest that CRT may not be necessary in PGR T-ALL patients with a WBC count less than 100,000/microL; on the contrary, in patients with a high count, extended T.I.T. may be inferior to CRT and I.T. MTX.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irradiação Craniana , Leucemia-Linfoma de Células T do Adulto/terapia , Contagem de Leucócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prednisona/uso terapêutico , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Daunorrubicina/administração & dosagem , Feminino , Humanos , Lactente , Injeções Espinhais , Leucemia-Linfoma de Células T do Adulto/sangue , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Recidiva , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor-recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II-IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse <30 months. The 2-year probability of EFS for children transplanted before and after 1 January 1998 was 27% (10-44) and 58% (42-75), respectively (P = 0.02), this difference remaining significant in multivariate analysis. EFS of unrelated donor HSCT in children with ALL in second CR has improved in the last few years, mainly due to a decreased TRM. This information is of value for counseling of patients with relapsed ALL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , DNA de Neoplasias/análise , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Lactente , Doadores Vivos , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prednisona/administração & dosagem , Sistema de Registros , Indução de Remissão , Taxa de Sobrevida , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
The first multicentric approach to childhood acute lymphoblastic leukemia (ALL) treatment in Italy started in the early 1970s when the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) was founded. Since then the AIEOP has conducted nationwide chemotherapy protocols. Results obtained in three different periods (1982-1986, 1987-1990, 1991-1995) are reported here. Treatment schedules have been characterized by a progressive intensification of systemic therapy and by a progressive substitution of protracted intrathecal therapy for cranial irradiation as central nervous system (CNS) preventive therapy. In the third period cranial radiotherapy (CRT) has been administered only to patients at high risk of relapse or with CNS involvement at diagnosis (about 15% of the overall population). A progressive improvement of therapeutic results, with a steady reduction of isolated CNS relapse rates have been obtained in the three periods considered here. The AIEOP experience shows that CRT can be safely omitted in non-high risk patients, unless they are T-ALL patients with WBC count at the diagnosis > or =100,000/mm3, and that intensification of treatment allows the improvement of overall results with a reduction of the impact of NCI prognostic criteria. Over the years, AIEOP has also continued to foster active cooperation at an international level. In the ongoing AIEOP ALL 2000 study, conducted in cooperation with the BFM group, patients are stratified according to the presence of translocations t(9;22) and t(4;11) and to treatment response (either initial steroid therapy or induction) or minimal residual disease). This cooperation will allow an adequate recruitment of patients to answer relevant randomized questions in the context of a study in which patients are stratified according to minimal residual disease findings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , HumanosRESUMO
Additional chromosomal aberrations occur frequently in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) of childhood. The treatment outcome of these patients is heterogeneous. This study assessed whether such clinical heterogeneity could be partially explained by the presence and characteristics of additional chromosomal abnormalities. Cytogenetic descriptions were available for 249 of 326 children with Ph+ ALL, diagnosed and treated by 10 different study groups/large single institutions from 1986 to 1996. Secondary aberrations were present in 61% of the cases. Chromosomes 9, 22, 7, 14, and 8 were most frequently abnormal. Most (93%) karyotypes were unbalanced. Three main cytogenetic subgroups were identified: no secondary aberrations, gain of a second Ph and/or >50 chromosomes, or loss of chromosome 7, 7p, and/or 9p, while other secondary aberrations were grouped as combinations of gain and loss or others. Of the three main cytogenetic subgroups, the loss group had the worst event-free survival (P=0.124) and disease-free survival (P=0.013). However, statistical significance was not maintained when adjusted for other prognostic factors and treatment. Karyotypic analysis is valuable in subsets of patients identified by molecular screening, to assess the role of additional chromosomal abnormalities and their correlation with clinical heterogeneity, with possible therapeutic implications.
Assuntos
Aberrações Cromossômicas , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Quebra Cromossômica , Deleção Cromossômica , Análise Citogenética , Intervalo Livre de Doença , Feminino , Heterogeneidade Genética , Humanos , Funções Verossimilhança , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
We investigated the cytotoxic activity and some aspects of the mode of action of 5-aza-2'-deoxycytidine (Aza-dC) in 21 primary cultures of leukemic cells freshly obtained from patients with chronic myeloid leukemia (CML) in blast crisis. The cytotoxic potency of Aza-dC was comparable or even greater than that of 1-beta-D-arabinofuranosylcytosine (Ara-C) in most cases, suggesting that this drug has potential in the therapy of blast crisis of CML. Drug incorporation into DNA was evaluated by exposing leukemic cells simultaneously to 3H-Aza-dC at the concentration of 0.1 micrograms/ml and 14C-thymidine (TdR) used as internal standard. Incorporation of Aza-dC into DNA was detectable in all cases. In 17 samples we evaluated the DNA integrity of leukemic cells exposed to Aza-dC using alkaline elution techniques. The drug caused a detectable amount of DNA alkali labile sites (ALS). DNA-ALS increased in cells exposed to Aza-dC concentrations from 0.1 to 1 microgram/ml but did not further increase at 10 micrograms/ml. A plateau in the levels of DNA-ALS was also seen in human K562 cells exposed to increasing concentrations of Aza-dC from 5 to 10 micrograms/ml, whereas in these cells Aza-dC incorporation into DNA increased with increasing Aza-dC concentrations. Therefore, DNA-ALS caused by Aza-dC are not simply the result of the chemical decomposition of azacytosine molecules incorporated into DNA, but are presumably the result of a saturable DNA repair mechanism (e.g., glycosylases) leading to formation of the apyrimidinic sites.
Assuntos
Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Crise Blástica , Citarabina/farmacologia , DNA de Neoplasias/metabolismo , Decitabina , Humanos , Fatores de Tempo , Células Tumorais CultivadasRESUMO
We investigated m-AMSA or doxorubicin (Dx) induced DNA single-strand breaks (DNA-SSB) in myeloid leukemia cells obtained from 8 adult patients suffering from AML. Highly purified AML cells were stimulated to proliferate with the addition of the appropriate growth factor (GCT) and exposed to different concentrations of m-AMSA or Dx for 1 or 4 h, respectively. DNA-SSB were determined by alkaline elution techniques. Either the kinetics or the amounts of DNA-SSB caused by both topoisomerase II inhibitors were variable among different cases. By increasing m-AMSA concentrations there was a concomitant increase in DNA-SSB up to a plateau at the highest concentrations. Dx induced DNA-SSB followed a bell shape curve with a decrease in the number of breaks at the highest concentrations that was evident in most cases. The interindividual variability of Dx-induced DNA-SSB was not correlated with intracellular Dx concentrations as assessed by flow cytometry. No correlation was evident between the amount of DNA breaks induced by m-AMSA and that induced by Dx. These data suggest that AML cells derived from different patients are not necessarily cross-sensitive or cross-resistant to topoisomerase II inhibitors with different chemical structures such as amsacrine or anthracyclines.
Assuntos
Amsacrina/farmacologia , Dano ao DNA , DNA de Cadeia Simples/efeitos dos fármacos , Doxorrubicina/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-IdadeRESUMO
The early toxicity, incidence of graft-versus-host disease (GVHD) and long-term follow-up were evaluated in two children with Down syndrome (DS) treated for acute lymphoblastic leukemia (ALL) in second complete remission by HLA-matched sibling allogeneic bone marrow transplantation (BMT). Preparative conditioning therapy consisted of cytosine arabinoside (Ara-C) and fractionated total body irradiation (F-TBI) and GVHD prophylaxis of cyclosporin A. The conditioning regimen was well tolerated, the only acute complication being mild mucositis. Engraftment (polymorphonuclear cells >500/microliter) was documented by day +17 in both patients. One child remains in continuous complete remission, without medical problems, 60 months after BMT. The second patient died from complications associated with chronic GVHD 21 months following BMT. Ara-C and F-TBI is a well-tolerated preparative regimen for children with DS undergoing allogeneic BMT.
Assuntos
Transplante de Medula Óssea , Citarabina , Síndrome de Down/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Irradiação Corporal Total , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Terapia Combinada , Irradiação Craniana , Daunorrubicina/administração & dosagem , Evolução Fatal , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/radioterapia , Prednisona/administração & dosagem , Terapia de Salvação , Transplante Homólogo , Vincristina/administração & dosagemRESUMO
The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox's regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). In the ALLO group four out of nine patients were in CCR 4-5 years post-transplant. This study suggests that ABMT may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd CR after an early isolated CNS relapse.
Assuntos
Transplante de Medula Óssea , Neoplasias Meníngeas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias Meníngeas/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Transplante AutólogoRESUMO
Plasma pharmacokinetics of VP16-213 were investigated after a 30-60 min infusion in 14 adult patients and six children. In adult the elimination half-life (T1/2 beta), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05 +/- 0.67 h, 26.8 +1- 2.4 ml/min/m2, and 15.7 +1- 1.8 l/m2; in children 3.37 +/- 0.5 h, 39.34 +1- 6.6 ml/min m2, and 9.97 +/- 3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20-30% of the dose. In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose. Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m2/24h) were around 2-5 micrograms/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.