RESUMO
PURPOSE: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon. PATIENTS AND METHODS: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis. RESULTS: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen - total body irradiation or busulfan - exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT. CONCLUSION: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Antineoplásicos/uso terapêutico , Benzamidas , Purging da Medula Óssea , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Piperazinas/uso terapêutico , Estudos Prospectivos , Pirimidinas/uso terapêutico , Condicionamento Pré-Transplante/métodos , Transplante HomólogoRESUMO
Fatal problems encountered in allogeneic stem cell transplantation include EBV reactivation and post transplant lymphoproliferative disorders (PTLDs) with high mortality rates. We performed a retrospective analysis in all consecutive adult and pediatric EBV reactivations and PTLD during a period of 8.5 years. There were 26 patients with EBV reactivation/PTLD out of a total of 854 transplantations giving an overall incidence of 3.0%. Specifically, the incidence of EBV-PTLD was 1.3%, whereas that of EBV reactivation was 1.8%. Median age was 46.0 and 11.0 years in the adult and pediatric patients, respectively. There were high rates (54%) of concomitant bacterial, viral, fungal and parasitic infections at the time of EBV manifestation. Variable treatment regimens were applied including in most cases an anti-CD20 regimen often in combination with virustatic compounds, polychemotherapy or donor lymphocytes. The mortality rates were 9 of 11 (82%) in patients with EBV-PTLD and 10 of 15 (67%) in patients with reactivation. Only 7 of 26 patients (27%) are alive after a median follow-up of 758 days (range 24-2751). The high mortality rates of EBV reactivation and of EBV-PTLD irrespective of multimodal treatment approaches emphasize standardization and optimization of post transplant surveillance and treatment strategies to improve control of these often fatal complications.
Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4/crescimento & desenvolvimento , Transplante de Células-Tronco/efeitos adversos , Ativação Viral , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Infecções Bacterianas/epidemiologia , Criança , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Doença Enxerto-Hospedeiro/epidemiologia , Teste de Histocompatibilidade , Humanos , Terapia de Imunossupressão , Pessoa de Meia-Idade , Micoses/epidemiologia , Doenças Parasitárias/epidemiologia , Doadores de TecidosRESUMO
We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia=25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n=22; TBI/Cy/VP, n=17; others, n=5) followed by marrow or peripheral blood transplant (n=23/21) from unrelated or related donors (n=28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n=15) and infections (n=12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts < or =20% and time to transplant < or =1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with < or =20% marrow blast.
Assuntos
Crise Blástica/terapia , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Crise Blástica/complicações , Crise Blástica/mortalidade , Crise Blástica/patologia , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Retrospectivos , Transplante Homólogo , Irradiação Corporal Total/métodosRESUMO
We report the results of 84 patients with ALL after related (n = 46) or unrelated (n = 38) allogeneic SCT. Mean recipient age was 23 years (range: 1-60) and median follow-up was 18 months (range: 1-133). Forty-three patients were transplanted in CR1; 25 in CR2 or CR3; four were primary refractory; four in PR; eight in relapse. The conditioning regimen consisted of TBI/VP16/CY (n = 76), TBI/VP16 (n = 2), TBI/CY (n = 2), Bu/VP16/CY (n = 4). The OS at 3 years was 45% (44% unrelated, 46% related). Univariate analysis showed a significantly better OS for patients <18 years (P=0.03), mismatched sex-combination (P = 0.03), both with a stronger effect on increasing OS after unrelated SCT. Factors decreasing TRM were patient age <18 years (P = 0.004), patient CMV-seronegativity (P = 0.014), female recipient (P = 0.04). There was no significant difference in TRM and the relapse rate was similar in both donor type groups. Multivariate analysis showed that factors for increased OS which remained significant were mismatched sex-combination (RR: 0.70,95% CI: 0.51-0.93, P = 0.015), patient age < 18 years (RR: 0.66, 95% CI: 0.47-0.93, P = 0.016). A decreased TRM was found for female patients (RR: 0.56, 95% CI: 0.33-0.98, P=0.042), negative CMV status of the patient (RR: 0.57, 95% CI: 0.36-0.90, P = 0.015). Unrelated stem cell transplantation for high-risk ALL patients with no HLA-compatible family donor is justifiable.
Assuntos
Seleção do Doador , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Intervalo Livre de Doença , Seleção do Doador/métodos , Feminino , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante HomólogoRESUMO
A total of 1111 children with acute myeloblastic leukaemia (AML) were treated in four consecutive Berlin-Frankfurt-Münster (BFM) studies from 1978 to 1998. The first cooperative trial AML-BFM 78 established intensive chemotherapy with seven drugs, CNS irradiation and 2-year maintenance, achieving a long-term survival (overall survival (OS)) of 40%. Induction intensification in AML-BFM 83 resulted in significant improvement of disease-free survival (DFS). The risk of haemorrhage, especially in children with hyperleukocytosis, proved the high relevance of supportive care. In AML-BFM 87, the benefit of CNS irradiation in preventing CNS/systemic relapses was demonstrated. In AML-BFM 93, the introduction of idarubicin during first induction followed by intensification with HAM increased the 5-year EFS, DFS and OS to 50+/-2, 61+/-3 and 57+/-2%, respectively. Stem cell transplantation (SCT), as applied in high-risk patients with a matched related donor, did not significantly improve the outcome compared to chemotherapy alone. In spite of treatment intensification, the therapy-related death rate decreased from trial to trial, mainly during induction. The future aim is to reduce long-term sequelae, especially cardiotoxicity, by administration of less cardiotoxic drugs, and toxicity of SCT by risk-adapted indications. The AML-BFM studies performed in three European countries with >70 cooperating centres have significantly improved the outcome in AML children; nevertheless, increasing experience with these intensive treatment regimens is of fundamental importance to reduce fatal complications.
Assuntos
Protocolos Antineoplásicos/normas , Leucemia Mieloide Aguda/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Irradiação Craniana , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Hemorragia/etiologia , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Indução de Remissão/métodos , Medição de Risco , Prevenção Secundária , Resultado do TratamentoRESUMO
This is a case report of a 4 1/2-year-old boy who developed acute monoblastic leukemia 2 1/2 years after he had been treated successfully with combined chemotherapy for neuroblastoma. All analyzable bone marrow-derived metaphases had the karyotype 47,XY, + 8,t(9;11)(p21;q23). The rare occurrence of specific chromosomal translocations in leukemias following prior chemotherapy and/or radiotherapy and their possible clinical implications in such cases are discussed.
Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Monocítica Aguda/induzido quimicamente , Neuroblastoma/tratamento farmacológico , Translocação Genética , Doença Aguda , Neoplasias das Glândulas Suprarrenais/patologia , Medula Óssea/ultraestrutura , Pré-Escolar , Humanos , Cariotipagem , Leucemia Monocítica Aguda/genética , Masculino , Neuroblastoma/patologiaRESUMO
Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Análise Atuarial , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Neoplasias Ósseas/cirurgia , Criança , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Osteossarcoma/cirurgia , Período Pós-Operatório , Cuidados Pré-Operatórios , Prognóstico , Distribuição AleatóriaRESUMO
PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P =.01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P =.007; and 44% v 31%, P =.01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Daunorrubicina/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/mortalidade , Masculino , Mitoxantrona/administração & dosagem , Fatores de Risco , Taxa de SobrevidaRESUMO
A variety of oncogenes are activated by specific chromosomal translocations, which are associated with distinct subtypes of leukemia. The identification of these rearrangements provides critical diagnostic and prognostic information, which may contribute to the selection of specific anti-leukemic therapy. The translocation t(9;22), the equivalent of the BCR/ABL rearrangement, is associated with a poor prognosis. We therefore used RT-PCR to detect this molecular event in a prospective study including 890 children. 673 of them suffered from acute lymphoblastic leukemia (ALL) at primary diagnosis and a transcription of the chimeric gene was detected in 21 of 648 with a successful analysis (3.2%). All children were treated by one of the two German multicenter childhood ALL therapy studies ALL-BFM-90 or COALL-05-92, respectively. Comparison of clinical features between BCR/ABL-positive and -negative children showed no significant differences regarding WBC, percentage of blasts, splenomegaly, hepatomegaly and age. Immunophenotypic studies at diagnosis in 21 BCR/ABL-positive children identified common ALL in 16 patients (76.2%), pre-B-ALL in four (19.0%), and an early T-lineage ALL in one (4.8%). Coexpression of myeloid antigens (CD13 and/or CD33) was observed in six of 16 common ALL patients as well as in the one child with early T-lineage ALL phenotype. The type of breakpoint (m-BCR/ABL: n = 14; M-BCR/ABL: n = 7) showed no correlation with clinical parameters. A comparison of cytogenetic and molecular data was performed in 16 positive patients and was concordant in all of them. We analyzed the response to the prednisone pretreatment and found a higher incidence of poor responders among the BCR/ABL-positive children. Regarding the event-free survival (EFS) of BCR/ABL-positive (0.53) and -negative patients (0.79) after a follow-up of 2 years, significant differences (P < 0.05) between both groups could be demonstrated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Asparaginase/administração & dosagem , Sequência de Bases , Criança , Pré-Escolar , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 9 , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Alemanha , Humanos , Incidência , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Transcrição Gênica , Translocação Genética , Vincristina/administração & dosagemRESUMO
We explored the combination of busulfan/cyclophosphamide/etoposide as conditioning regimen prior to bone marrow transplantation in 31 patients with acute myeloid leukemia (AML) in first complete remission. The preparative regimen consisted of 16 mg/kg busulfan, 30-60 mg/kg VP-16, and 120 mg/kg cyclophosphamide. With a median follow-up of 30.5 months (range, 5-60 months), 25 patients are alive in continuous complete remission. Estimated disease-free survival at 5 years is 80.5%. Death was due to transplant-related toxicity (graft-versus-host disease and cytomegalovirus infection, graft-versus-host disease and pneumonia, sepsis and mucositis, respectively). None of the patients have relapsed. As demonstrated by the results of this analysis, the conditioning regimen busulfan/cyclophosphamide/etoposide is effective and well tolerated in patients with AML in first complete remission. Main nonhematological toxicities were mucositis and hepatotoxicity. The low mortality and relapse rate appears to justify allogeneic bone marrow transplantation for patients with AML in first complete remission who have an HLA-identical donor. Whether this regimen offers a substantial improvement in disease-free and overall survival over presently used regimens warrants further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Etoposídeo/efeitos adversos , Leucemia Mieloide/terapia , Doença Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Masculino , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Indução de Remissão , Fatores de Tempo , Transplante HomólogoRESUMO
The time it takes to harvest bone marrow before transplantation could be reduced significantly by increasing the temperature of the operating room by 8-10 degrees C, to about 28-30 degrees C. In healthy donors, the collected volume of marrow was increased from 22.45 to 36.31 mL/min; in patients who received chemotherapy previously, from 21.67 to 29.98 mL/min. The time to collect a volume of 1200 mL marrow could be reduced significantly, from 57.78 to 38.25 minutes in healthy donors and from 71.07 to 43.36 minutes in patients who received chemotherapy previously, without any loss of quality of the sampled marrow. Operation time and thereby time of anesthesia could be reduced significantly by heating the operating room to a temperature of 28-30 degrees C. Harvesting at higher room temperature did not result in any adverse side effects for the patients. The procedure to increase the body temperature could be simplified by using electric blankets and aluminum foils for wrapping to avoid heat emission.
Assuntos
Células da Medula Óssea , Temperatura Alta , Manejo de Espécimes/métodos , Doadores de Tecidos , Adolescente , Adulto , Temperatura Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Rearrangement of the gene tal-1 leads to transcriptional dysregulation and contributes to the formation of childhood T-cell acute lymphoblastic leukemia. Therefore, we tried to interfere with the transcription of the SIL/tal-1 fusion gene, the most common form of aberrant tal-1, by treatment with antisense oligodeoxynucleotides (ODNs). The potential of two different strategies was investigated, one targeting the cell line specific SIL/tal-1 fusion region, the other using an ODN complementary to tal-1 sequence downstream of the region not affected by any of the known types of tal-1 rearrangement. With both approaches a single-dose application of 3 mumol of ODN led to a significant antiproliferative effect of a about 25-60% in two T-ALL cell lines characterized by the SIL/tal-1 fusion gene. Investigation of the tal-1 mRNA level by reverse transcription-polymerase chain reaction was in concordance with these results: In both cell lines clearly less of the tal-1-specific fragment was generated after incubation with the antisense ODN tal-1 common than in the control experiments with a mismatched ODN or no ODN at all. Neither the antiproliferation antisense effect nor the downregulation of the steady state tal-1 mRNA level was observed in control cell lines bearing wildtype tal-1.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/genética , Oligonucleotídeos Antissenso/farmacologia , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas , Fatores de Transcrição , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Divisão Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucemia-Linfoma de Células T do Adulto/patologia , Mutação , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacocinética , Proteínas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/efeitos dos fármacos , Proteínas Recombinantes de Fusão/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Células Tumorais CultivadasRESUMO
Between January 1986 and May 1996, 870,313 children were tested in European neuroblastoma (NB) screening programmes. Among these children, 82 cases of NB (age range 4-24 months, median 11 months) were detected by screening. 83% of the patients had localised NB and 17% were diagnosed with generalised NB (stage 4, 10%; stage 4s, 7%). Unfavourable biological markers (MYCN amplification, loss of heterozygosity (LOH) 1p36, DNA di/tetraploidy) were observed in 14% of 76 biologically examined cases. The median follow-up time of all the patients was 21.5 months (range 1-101 months). To date, 69 patients are in complete remission (CR) and 2 patients have died due to therapy (stage 4, 1 patient; stage 3, 1 patient with unfavourable markers). Apart from screened patients, 16 other patients with NB were found who had previously had a normal screening test, i.e. 'false negative' patients (age range 10-41 months, median 31.5 months). The median interval between screening and diagnosis was 24.5 months (range 6-35 months). 11 of the 'false negative' patients suffered from generalised NB (stage 4) and 5 had localised NB at diagnosis. Unfavourable biological markers were observed in 7/12 patients. 5 patients have died, 2 achieved partial remission and 9 CR. 9 of the 11 patients with unfavourable biological markers diagnosed due to NB screening are currently in CR. It is very likely that, among the patients without unfavourable biological markers, we detected tumours which may have regressed spontaneously. These children may have undergone 'unnecessary,' but unavoidable, diagnostic procedures and therapy. To reduce the number of 'false negative' patients, a later screening could be helpful and should be evaluated.
Assuntos
Programas de Rastreamento/normas , Neuroblastoma/prevenção & controle , Distribuição por Idade , Biomarcadores Tumorais , Pré-Escolar , Europa (Continente) , Genes myc , Humanos , Lactente , Perda de Heterozigosidade , Neuroblastoma/genética , Ploidias , Prognóstico , Fatores de Risco , Sensibilidade e Especificidade , Distribuição por Sexo , Análise de SobrevidaRESUMO
In a cell-free translation directed mRNA from the human lymphoblastoid cell line KM3, common ALL-Antigen (CALLA)-like proteins were detected immunologically. For immunoprecipitation a combination of three monoclonal antibodies and a rabbit heteroantiserum with anti-CALLA specificity were used. Employing a cocktail of two anti-CALLA monoclonal antibodies CALLA directing mRNA could be purified by specific polysomal immunoadsorption. The CALLA-like protein defined in the cell-free products of total mRNA and mRNA derived from polysomes showed a Mr of 95,000 daltons. Additional CALLA-like proteins could be identified in the cell-free translational products when mRNA from polysomes precipitated by the anti-CALLA heteroantiserum was used. The calculated Mr of these proteins were 80,000 97,000 and 135,000 daltons.
Assuntos
Antígenos de Neoplasias/genética , Biossíntese de Proteínas , RNA Mensageiro/isolamento & purificação , Animais , Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/imunologia , Sistema Livre de Células , Humanos , Peso Molecular , Neprilisina , Polirribossomos/metabolismo , CoelhosRESUMO
In the present study the complication rate of Broviac catheters in the therapy of children with cancer was determined. Of special interest was the question of to what extent the incidence of bacteremias is increased by the implant. For this reason the method of matched pairs analysis was chosen comparing 55 patients with 61 catheters to 1 child each who received the therapy via peripheral veins. Apart from having the same disease, the same therapy protocol and the same age group the partners had a similar number of leukocytopenic days (leukocyte counts, < 1000/microliters) in the study period. The observation time was 9671 days in the catheter group and 9666 days in the control group. During this time 167 fever episodes (17.7 episodes/1000 days) were recorded in the patients with implant but only 133 episodes (14.0/1000 days) in the control patients. Study and control groups had similar frequencies of fever of unknown origin with leukocyte counts > or = 1000/microliters and fever with a known focus. However, 29 bacteremias (2.9 episodes/1000 days) represented a 4 times higher complication rate with the use of Broviac catheters than in the control group (7 bacteremias, 0.7 episode/1000 days). Episodes of fever of unknown origin with leukocytopenia were 1.5 times more common in the catheter group than in the control group. Although it is not possible to prove that the catheter played a role as focus of bacterial infection, an increased risk of infection must be supposed. The Broviac catheter meets with broad approval by the patients, parents and medical staff.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Bacteriemia/etiologia , Cateteres de Demora/efeitos adversos , Neoplasias/tratamento farmacológico , Estudos de Casos e Controles , Criança , Humanos , Injeções Intravenosas/efeitos adversos , Análise por Pareamento , Estudos RetrospectivosRESUMO
Use of cryopreserved donor bone marrow may facilitate scheduling of allogeneic bone marrow transplantation (BMT) by affording independence of a fixed time for bone marrow donation. The potential risk of damage to hematopoietic stem cells by cryopreservation resulting in delayed engraftment or graft failure has to be taken into account, however. To address these issues, the outcome of 19 matched related BMT (1992-94) performed with cryopreserved donor bone marrow was analyzed and compared with 19 related BMT (1990-93) receiving fresh donor bone marrow (control group). Time to engraftment of patients receiving cryopreserved bone marrow was not different from the control group (ANC > 0.2 x 10(9)/l 15.5 +/- 3.8 days vs 15.8 +/- 5.0 days; ANC > 0.5 x 10(9)/l 17.3 +/- 4.1 days vs 17.9 +/- 5.0 days, respectively). We did not find the previously described trend toward a lower incidence of acute GVHD in patients receiving cryopreserved bone marrow compared with patients receiving fresh bone marrow (acute GVHD > or = II 78 vs 64%). Furthermore, the two groups did not differ in the incidence of chronic GVHD (55 vs 38%) or day 100 survival (74 vs 68%). We conclude that in allogeneic BMT cryopreserved bone marrow cells can be safely used without jeopardising or prolonging time to engraftment.
Assuntos
Células da Medula Óssea , Transplante de Medula Óssea , Criopreservação , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doenças Hematológicas/mortalidade , Doenças Hematológicas/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
Based on encouraging results of a recently published study on the clinical usefulness of oral pentoxifylline (PTX) to reduce transplant-related toxicities, prophylactic pentoxifylline was administered to 31 consecutive allogeneic BMT recipients with hematological malignancies. Patients received PTX as a continuous infusion at increasing dose levels (0.50, 0.75, 1.00 and 1.25 mg/kg/h) starting 1 day prior to the conditioning regimen. At all dose levels, PTX was well tolerated with no significant side-effects. When compared with a historical control group of 61 consecutively transplanted allogeneic BMT recipients, PTX patients did not appear to experience less gastrointestinal (moderate and severe mucositis: 100% vs 68%, p < 0.001), hepatic (hyperbilirubinemia > 1.5 mg/dl: 84% vs 30%, p < 0.001) or renal (creatinine > 1.5 mg/dl: 16% vs 27%, NS) toxicity or to have a lower incidence of GVHD > or = grade III (21% vs 22%, NS). Using i.v. PTX, we were unable to reproduce the reduction in morbidity and mortality in patients undergoing BMT which has been described for prophylactic oral PTX.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Pentoxifilina/uso terapêutico , Adolescente , Adulto , Purging da Medula Óssea/efeitos adversos , Bussulfano , Criança , Ciclofosfamida , Etoposídeo , Gastroenteropatias/induzido quimicamente , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Hiperbilirrubinemia/induzido quimicamente , Incidência , Infusões Intravenosas , Nefropatias/induzido quimicamente , Pessoa de Meia-Idade , Pentoxifilina/administração & dosagem , Pentoxifilina/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Fator de Necrose Tumoral alfa/biossíntese , Irradiação Corporal TotalRESUMO
115 patients undergoing allogeneic or autologous bone marrow or peripheral blood stem cell transplantation were treated empirically or for documented fungal infection with liposomal amphotericin-B in doses up to 10mg/kg bodyweight for a duration up to 61 days. The therapy was excellent tolerated and clinical side effects occurred in only eight patients. The drug had to be withdrawn in one episode. A significant influence of liposomal amphotericin-B on laboratory parameters was not observed. Creatinine increased under therapy from a median base point of 1,0 (0,2-3,5) mg/dl to the upper normal value of 1,4 (0,4-4,2) mg/dl. Heavy increases of creatinine as well as of bilirubin, OT and PT were mostly associated with GvHD or regimen related toxicity. Considering the high-risk state of the patients the overall response rate was favourable with 62,9%. However, despite administration of liposomal amphotericin-B culture-proven mycoses were associated with a high morbidity (93,3%). Only one of fourteen patients was cured from Candida lambica septicaemia. We conclude that the antimycotic therapy with liposomal amphotericin-B has a low incidence of side effects. This should, considering the high mortality of fungal infections in BMT recipients, encourage investigators to perform dose escalating studies against the conventional formulation.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Micoses/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia/complicações , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Micoses/complicaçõesRESUMO
We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Adulto , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/mortalidade , Anemia Refratária com Excesso de Blastos/patologia , Anemia Refratária com Excesso de Blastos/terapia , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/efeitos adversos , Medula Óssea/patologia , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Contagem de Células , Cromossomos Humanos Par 7/genética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Estudos de Viabilidade , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/mortalidade , Histocompatibilidade , Humanos , Infecções/etiologia , Infecções/mortalidade , Cariotipagem , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Monossomia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Recidiva , Taxa de Sobrevida , Linfócitos T , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento , Vidarabina/efeitos adversosRESUMO
We compared fractionated total body irradiation (12 Gy)/cyclophosphamide (120 mg/kg) with busulfan (16 mg/kg)/cyclophosphamide (120 mg/kg) as preparative therapy in unrelated donor stem cell transplantation of CML patients. Fifty patients with CML (1.CP = 46; aP = 4) and a median age of 36 years (range 16-52) were enrolled in this sequential trial between 1994 and 1999. In both groups patients were well balanced with respect to age, disease status, stem cell source and CMV status. All patients received standard doses of cyclosporin A, methotrexate and anti-thymocyte globulin (ATG) as GVHD prophylaxis. No graft failures occurred in either group. The median day of leukocyte engraftment was earlier in the Bu/Cy than in the TBI/Cy group (day 15 vs 17; P = 0.006). The incidence of grade II-IV GVHD was 40% in the TBI/Cy and 36% in the Bu/Cy group, whereas severe grade III/IV GVHD was only observed in 12% of patients in both groups. The incidence of chronic GVHD (limited and extensive) at 1 year was higher in the Bu/Cy arm (65% vs 30%; P = 0.02). More toxicity grade I/II of the liver (88% vs 44%; P = 0.002) and more hemorrhagic cystitis (32% vs 8%; P = 0.02) were observed in the Bu/Cy regimen. Seven relapses in the TBI and no relapse in the Bu/Cy group were observed after a median follow-up of 44 and 15 months, respectively. The estimated 3 year OS and DFS was 72% (95% CI: 55-98%) and 58% (95% CI: 39-77%) in the TBI and 70% (95% CI: 51-89%) for DFS and OS in the Bu/Cy group. We conclude that the anti-leukemic effect of the Bu/Cy regimen seems to be at least as effective as the TBI/Cy combination in unrelated stem cell transplantation of CML patients, with no graft failures, but that it correlates with a higher incidence of liver toxicity, hemorrhagic cystitis and chronic GVHD. Longer follow-up is necessary to determine the late relapse rate and late toxicity.