Asunto(s)

Sistema Enzimático del Citocromo P-450/genética , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Humanos , Datos de Secuencia Molecular

RESUMEN

Significant predictors of treatment outcome are poorly defined for patients with T-lineage acute lymphoblastic leukemia (T-ALL). A high WBC at diagnosis, which has traditionally been a predictor of poor response in T-ALL, has considerably weakened prognostic significance in the face of modern, more intensive chemotherapy. To test the hypothesis that bone marrow stroma-supported leukemic cell recovery might identify children at high risk for relapse, we measured the ex vivo recovery of T-ALL lymphoblasts from 29 newly diagnosed patients using a stromal cell co-culture assay. In all cases the T-ALL lymphoblasts showed an increase in recovery of T-ALL cells (RTC), ranging from 4 to 343%, in comparison to samples maintained without stroma. Since we were blinded to patient outcome in this case-control study, we then correlated patient outcome with RTC. The RTC for 18 patients in complete continuous remission (CCR) for greater than 4 years was stochastically larger than for the 11 patients who eventually relapsed (P = 0.011, by the two-sided Wilcoxon test). Furthermore, 100% of patients with an RTC of more than 26% had a CCR greater than 4 years while 78% of the patients with an RTC of less than 25% relapsed within 4 years. This is the first report to show that higher lymphoblast recovery may predict a more favorable outcome for children with T-ALL. A prospective study is needed to test whether stroma-supported leukemic cell recovery might serve as a basis for assigning risk-adjusted therapy.

Asunto(s)

Células de la Médula Ósea/citología , Técnicas de Cocultivo/métodos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Recurrencia Local de Neoplasia/diagnóstico , Células del Estroma/fisiología , Adolescente , Adulto , Estudios de Casos y Controles , Línea Celular , Linaje de la Célula , Supervivencia Celular , Niño , Preescolar , Humanos , Lactante , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/patología , Recuento de Leucocitos , Resultado del Tratamiento , Células Tumorales Cultivadas

RESUMEN

To further define the cytogenetic differences between B-cell lineage (B-lineage) acute lymphoblastic leukemia (ALL) and T-cell lineage ALL (T-ALL) and to determine the prognostic value of cytogenetics in childhood T-ALL, the blast cell karyotypes of 343 cases of pediatric T-ALL, the largest series reported to date, were evaluated. Cytogenetics were performed in a single central laboratory, and the children were treated using a single Pediatric Oncology Group protocol. Clear differences between the karyotypic characteristics of B-lineage ALL and T-ALL were confirmed. This study suggests that there may be survival differences associated with some T-ALL blast cell karyotypes. Better survival is associated with only normal karyotypes and with t(10;14) (translocation of chromosomes 10 and 14); worse survival is associated with the presence of any derivative chromosome. Two new recurring chromosome aberrations previously not reported in T-ALL were found: del(1)(p22) and t(8;12)(q13;p13). Ten aberrations found in this series, which were reported only once previously in T-ALL, can now be considered recurring abnormalities in T-ALL. All 12 of these new recurring aberrations are targets for discovery and characterization of new genes that are important in T-cell development and leukemogenesis.

Asunto(s)

Aberraciones Cromosómicas , Cariotipificación , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Adolescente , Adulto , Aneuploidia , Linfoma de Burkitt/genética , Niño , Preescolar , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 14 , Femenino , Humanos , Lactante , Leucemia-Linfoma de Células T del Adulto/mortalidad , Masculino , Pronóstico , Tasa de Supervivencia , Translocación Genética

RESUMEN

We have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.

Asunto(s)

Antiinflamatorios/administración & dosificación , Trasplante de Médula Ósea , Ciclosporina/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia/terapia , Metotrexato/administración & dosificación , Prednisona/administración & dosificación , Enfermedad Aguda , Adolescente , Adulto , Trasplante de Médula Ósea/efectos adversos , Niño , Preescolar , Método Doble Ciego , Enfermedad Injerto contra Huésped/etiología , Humanos , Lactante , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento

RESUMEN

The rapidity of response to induction therapy is emerging as an important prognostic factor in children and adolescents with acute lymphoblastic leukemia (ALL). We studied the relationship between rapidity of reduction in peripheral blood blast count and treatment outcome in children with T cell ALL (T-ALL). Initial systemic chemotherapy included prednisone, vincristine, doxorubicin and cyclophosphamide. A Cox analysis evaluated the correlation between the length of time that the peripheral blood absolute blast count (ABC) remained above 1000/mm3 following the start of treatment and event-free survival (EFS). Data were available for 281 patients. Patients for whom the ABC remained >1000/mm3 for 3 or more days following administration of intensive therapy had an estimated 5-year EFS of 34.2% (s.e. = 7.2) vs 58.3% (3.5) for those whose ABC was <1000/mm3 within 0-2 days, with a hazard ratio (HR) of failure of 2.03 (95% CI = 1.35-3.06, P < 0.001) for the slower responding patients. Pre-treatment of some type (usually with prednisone) occurred in 128 patients (average duration 1.7 days). When this was accounted for, patients with an ABC >1000/mm3 for 5 or more days following the start of treatment of any kind had a HR for failure of 2.27 (95% CI = 1.38-3.72, P < 0.001) compared to those responding within 0-4 days. Inclusion of other clinical and biological factors in a multivariate analysis did not alter the prognostic importance of slower blast clearance. Pediatric patients with T-ALL who have a circulating blast count >1000/mm3 at diagnosis and a relatively slower response to initial treatment are at increased risk of treatment failure. Rapidity of response may therefore be a clinically useful prognostic factor for patients with T-ALL.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/uso terapéutico , Crisis Blástica/sangre , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Adolescente , Crisis Blástica/patología , Niño , Intervalos de Confianza , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Humanos , Leucemia-Linfoma de Células T del Adulto/sangre , Leucemia-Linfoma de Células T del Adulto/mortalidad , Análisis Multivariante , Valor Predictivo de las Pruebas , Prednisona/administración & dosificación , Pronóstico , Análisis de Regresión , Inducción de Remisión , Vincristina/administración & dosificación

RESUMEN

Epipodophyllotoxin-associated secondary myeloid leukemia is a devastating complication of acute lymphoblastic leukemia (ALL) therapy. The risk factors for treatment-related myeloid leukemia remain incompletely defined. Genetic deficiencies in glutathione S-transferase (GST) activities have been linked to higher frequencies of a number of human malignancies. Our objective was to determine whether the null genotype for GSTM1, GSTT1, or both, was more frequent in children with ALL who developed treatment-related myeloid malignancies as compared to those who did not. A PCR technique was used to assay for the null genotype for GSTM1 and GSTT1 in 302 children with ALL, 57 of whom also subsequently developed treatment-related acute myeloid leukemia or myelodysplastic syndrome. Among children with ALL who did not develop treatment-related myeloid malignancies, the frequencies of GSTM1 and GSTT1 wild-type, GSTM1 null-GSTT1 wild-type, GSTM1 wild-type-GSTT1 null, and GSTM1 and GSTT1 null genotypes were 40%, 42%, 9% and 9%, respectively. The corresponding frequencies for patients who developed acute myeloid malignancies were 42%, 32%, 11% and 16%, respectively (P = 0.26). A statistically significant increase in the frequency of the GST null genotype was observed in male patients who developed myeloid malignancies as compared to male ALL control patients (P = 0.036), but was not observed in female patients (P = 0.51). Moreover, a logistic regression analysis of possible predictors for myeloid malignancies, controlling for gender and race, did not reveal an association of GSTM1 or GSTT1 null genotypes (P = 0.62 and 0.11, respectively) with treatment-related malignancies. Our data suggest that GSTM1 and GSTT1 null genotypes may not predispose to epipodophyllotoxin-associated myeloid malignancies.

Asunto(s)

Antineoplásicos Fitogénicos/efectos adversos , Glutatión Transferasa/genética , Leucemia Mieloide Aguda/inducido químicamente , Neoplasias Primarias Secundarias/inducido químicamente , Podofilotoxina/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Niño , Preescolar , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Genotipo , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/etnología , Leucemia Mieloide Aguda/genética , Masculino , Oxigenasas de Función Mixta/efectos de los fármacos , Oxigenasas de Función Mixta/metabolismo , Neoplasias Primarias Secundarias/enzimología , Neoplasias Primarias Secundarias/etnología , Neoplasias Primarias Secundarias/genética , Podofilotoxina/uso terapéutico , Reacción en Cadena de la Polimerasa/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Factores de Riesgo , Estados Unidos

RESUMEN

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.

Asunto(s)

Trasplante de Médula Ósea , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Trasplante Homólogo , Adulto , Niño , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Recurrencia

RESUMEN

Graft-vs.-host disease (GVHD) is a major predictor of outcome following allogeneic bone marrow transplantation (BMT). For patients alive at day 100 after BMT, the presence or absence of chronic GVHD is one of the most important determinants of survival and quality of life. We wished to determine the effects on chronic GVHD of two regimens used for the prophylaxis of acute GVHD: cyclosporine, methotrexate, and prednisone (CSA/MTX/PSE) and cyclosporine and prednisone (CSA/PSE). One hundred forty-nine evaluable patients were entered into the acute GVHD study. As of 31 March 1997, 63 months after the last patient underwent BMT, the median survival time was 4.5 years (range 0.09-9.9). The incidence of chronic GVHD was independent of the prophylactic regimen (55 vs. 54%), and extensive chronic GVHD occurred in 25 and 24% of patients receiving CSA/MTX/PSE and CSA/PSE, respectively. Of note, the median Karnofsky performance status of both groups was 100% (range 70-100%), reflecting the low incidence of extensive chronic GVHD. Survival rates free of chronic GVHD were 52 vs. 42% (p = 0.29) for patients receiving CSA/MTX/PSE vs. CSA/PSE. The incidence of relapse was also similar in both groups of patients. These data suggest that the combinations of CSA/MTX/PSE and CSA/PSE result in comparable chronic GVHD-free survival without an increase in leukemic relapse.

Asunto(s)

Ciclosporina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Metotrexato/uso terapéutico , Prednisona/uso terapéutico , Enfermedad Aguda , Adolescente , Adulto , Antiinflamatorios/uso terapéutico , Trasplante de Médula Ósea , Causas de Muerte , Niño , Preescolar , Enfermedad Crónica , Enfermedades Transmisibles/etiología , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Inmunosupresores/uso terapéutico , Lactante , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Leucemia/terapia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Recurrencia , Tasa de Supervivencia , Trasplante Homólogo

RESUMEN

Methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine and methionine and is deficient in a variety of cancers including T-cell acute lymphocytic leukemia (T-ALL). Previously, we reported that the MTAP gene was deleted in over 30% of T-ALL patients at both diagnosis and relapse. We now report that MTAP-primary T-ALL cells are more sensitive to the toxicity of L-alanosine, an inhibitor of de novo AMP synthesis, than are MTAP+ primary T-ALL cells. As measured by [3H]thymidine incorporation, DNA synthesis in all seven MTAP-primary T-ALL cells was inhibited by L-alanosine with a mean IC50 of 4.8+/-5.3 ILM (range, 0.3-11.3 microM). On the other hand, the IC50 for 60% (12 of 20) of MTAP+ primary T-ALL was 19+/-18 microM (range, 1.7-67 microM; P = 0.02), whereas the remaining 40% (8 of 20) had an IC50 of >80 microM4. Furthermore, normal lymphocytes and MTAP+ primary T-ALL cells were rescued from L-alanosine toxicity by the MTAP substrate 5'-deoxyadenosine, but MTAP-T-ALL cells were not. These results indicate that normal cells, which are intrinsically MTAP+, would be protected from L.-alanosine toxicity, whereas MTAP-tumor cells would be killed. Thus, our results support the use of L-alanosine alone or in combination with a salvage agent as a MTAP-selective therapy and therefore lay the foundation for the initiation of clinical trials for the treatment of T-ALL and other MTAP-deficient malignancies with L-alanosine.

Asunto(s)

Antibióticos Antineoplásicos/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Purina-Nucleósido Fosforilasa/metabolismo , Adenosina Monofosfato/biosíntesis , Alanina/análogos & derivados , Alanina/uso terapéutico , Humanos , Leucemia-Linfoma de Células T del Adulto/metabolismo , Reacción en Cadena de la Polimerasa , Purina-Nucleósido Fosforilasa/deficiencia , Purina-Nucleósido Fosforilasa/genética , Timidina/metabolismo

RESUMEN

This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25,000 IU/m2) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50,000/microl or patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.

Asunto(s)

Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/administración & dosificación , Asparaginasa/uso terapéutico , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Inducción de Remisión

RESUMEN

This descriptive study of health-related quality of life of children with cancer compared children/adolescents', parents' and teachers' ratings for somatization, depression and anxiety to determine if there were significant correlations among respondent scores. In addition, the percentage of agreement among respondents and significant differences based on age, gender, use of cranial radiation and treatment status were measured. Forty-three children/adolescents with cancer, currently receiving therapy for at least 1 year or who had completed therapy for no more than 3 years (excluding children who had received bone marrow transplants or who had brain tumors), were recruited, with a parent and teacher, from 3 university medical centers. The Behavioral Assessment System for Children questionnaires for children/adolescents, parents and teachers were used. Parents reported a higher level of depression for the children/adolescents with cancer than did the teachers or the children/adolescents themselves. Parents reported a higher level of anxiety for the children/adolescents than did the teachers. High positive correlations were found among scores from parents and teachers and among scores from parents and children/adolescents for the anxiety and depression but not somatization subscales. Children/adolescents and teachers had high, positively correlated scores only for the depression subscale. High, positive correlations were found between somatization, anxiety and depression within each group of respondents. A significant percentage of agreement between all respondents on ratings for at-risk status was obtained only for the depression subscale. Age was the only variable found to have an influence on scores and only for the anxiety subscale.

Asunto(s)

Ansiedad/etiología , Depresión/etiología , Estado de Salud , Neoplasias/psicología , Calidad de Vida , Trastornos Somatomorfos/etiología , Adolescente , Niño , Femenino , Humanos , Masculino

Asunto(s)

Trasplante de Médula Ósea/fisiología , Talasemia beta/terapia , Adolescente , Adulto , Trasplante de Médula Ósea/inmunología , Busulfano/uso terapéutico , Niño , Preescolar , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Crecimiento , Humanos , Inmunosupresores/uso terapéutico , Lactante , Masculino , Probabilidad , Tasa de Supervivencia , Quimera por Trasplante , Talasemia beta/mortalidad , Talasemia beta/fisiopatología

RESUMEN

PURPOSE: The purpose of this study was to investigate the role of bone marrow transplant (BMT) early in the course of disease for pediatric patients with high-risk leukemia using a preparatory regimen of fractionated total body irradiation (FTBI) and etoposide (VP-16). PATIENTS AND METHODS: Those studied were 33 patients aged < or =18 years with either acute leukemia in first complete remission (CR) (n = 29) or chronic myelogenous leukemia (CML) in first chronic phase (n = 4) who received 1,320 cGy FTBI followed by high-dose VP-16 (60 mg/kg) as a preparatory regimen for BMT from matched sibling donors. Patients with acute leukemia included 18 with acute nonlymphocytic leukemia (ANLL), one with biphenotypic acute leukemia (BAL), and 10 with selected "high-risk" acute lymphocytic leukemia (ALL). Patients with ALL were selected for a high risk for recurrence: those who failed standard remission induction chemotherapy, had a t(9;22) or t(4;11) chromosomal translocation, or had certain clinical high-risk features. RESULTS: At the time of analysis, 28 patients are alive, all of them in continued complete remission for 1.1-7.8 years (median, 5.3 years; mean, 4.9 years). The Kaplan-Meier projected event-free survival (EFS) is 84.5% at 7 years, and the actuarial recurrence hazard is 6.5%. All surviving patients have a performance status of >80%. CONCLUSION: This result of early BMT in a two-institution study of pediatric patients with hematopoietic malignancies suggests that (a) matched sibling allogeneic BMT after conditioning with FTBI and high-dose VP-16 is an excellent treatment for pediatric patients with high-risk leukemia, and (b) children may have a better prognosis than adults treated with allogeneic BMT. Larger multiinstitutional cooperative trials for pediatric patients are needed to confirm this result.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Trasplante de Médula Ósea , Etopósido/uso terapéutico , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Femenino , Neoplasias Hematológicas/fisiopatología , Humanos , Lactante , Masculino , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento

RESUMEN

PURPOSE: To determine the effect of age on the outcome of autologous bone marrow transplantation (ABMT) and/or peripheral-blood progenitor-cell (PBPC) transplantation. PATIENTS AND METHODS: A retrospective analysis was performed on 500 consecutive patients who ranged in age from 1 to 65 years (median, 40) with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), multiple myeloma (MM), or acute nonlymphoblastic leukemia (AML) who underwent autologous hematopoietic-cell transplant procedures at Stanford University Medical Center. RESULTS: The actuarial 5-year event-free survival (EFS) rate was 44%, the relapse rate 47%, and the regimen-related mortality (RRM) rate 8.6%. Disease status at time of transplantation, categorized as either minimal or advanced disease, was the strongest predictive factor for EFS (relative risk (RR) for advanced-disease group, 1.8; P < .0003) and relapse rate (RR for advanced-disease group, 1.9; P < .0004). Patients with minimal or advanced disease had an EFS rate of 48% and 30% and relapse rates of 43% and 72%, respectively. The EFS rate of patients less than 50 years verus > or = 50 years of age was 46% versus 34% (P = .03). Cox regression analysis showed that age was predictive for EFS (RR for patients 50 to 65 years, 1.4; P = .03). The actuarial RRM rate for these age groups was 7.4% versus 12.7% (P = .07), respectively. Multivariate analysis demonstrated that age (odds ratio [OR] for patients 50 to 65 years, 1.9; P < .05) and period of transplantation (OR for most recent years [1991 to 1995], 0.6; P = .06) were the most predictive factors for RRM. CONCLUSION: Although age greater than 50 years is associated with an inferior outcome following autologous hematopoietic-cell transplantation, it does not appear to be warranted to limit this potentially curative procedure based solely on age. The upper age limit of high-dose therapy with autologous progenitor-cell and/ or bone marrow support remains to be defined.

Asunto(s)

Trasplante de Médula Ósea , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Distribución por Edad , Anciano , Niño , Preescolar , Enfermedad de Hodgkin/terapia , Humanos , Lactante , Leucemia Mieloide Aguda/terapia , Linfoma no Hodgkin/terapia , Persona de Mediana Edad , Mieloma Múltiple/terapia , Análisis Multivariante , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.

Asunto(s)

Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Etopósido/uso terapéutico , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Niño , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Irradiación Corporal Total

RESUMEN

The use of high-dose chemotherapy with or without total-body irradiation (TBI) followed by autologous hematopoietic cell transplantation is associated with improved survival for relapsed or refractory non-Hodgkin's lymphoma (NHL). Previous reports comparing preparatory regimens with or without TBI followed by autologous bone marrow transplantation (ABMT) or peripheral blood progenitor cell transplantation (PBPCT) for these patients did not demonstrate any survival difference between the different modalities. No randomized studies comparing survival for patients with NHL transplanted with radiochemotherapy vs. chemotherapy alone have been reported. We treated 221 patients with high-risk, relapsed or refractory NHL with either chemotherapy alone or radiochemotherapy followed by ABMT or PBPCT. The patients were assigned preparatory regimens in a non-randomized manner and this analysis was performed to evaluate differences in outcome with the two preparatory regimens. Actuarial five-year event-free survival (EFS) was similar in patients receiving fractionated total-body irradiation (FTBI) plus etoposide (VP-16) and cyclophosphamide (Cy) compared with chemotherapy alone consisting of carmustine (BCNU) plus identical doses of VP-16 and Cy (52% vs. 46%, p = 0.08). Overall survival (OS) favored radiochemotherapy (61%) compared with chemotherapy alone (53%, p = 0.02). The relapse rate was the same in both groups (41%), whereas the transplantation-related mortality (TRM) was similar in patients receiving chemotherapy alone and those receiving radiochemotherapy (13% vs. 7% respectively, p = 0.30). Proportional hazards analysis of significant variables including preparatory regimen found only the number of prior relapses to be predictive of EFS. Fewer number of prior relapses, radiochemotherapy and PBPCT were significant predictors of favorable OS. In additional analyses, the improved OS of the radiochemotherapy regimen was confirmed only for patients receiving ABMT but was not a significant predictor of outcome in patients transplanted with PBPCT. From these retrospective data we conclude: 1) PBPCT resulted in survival superior to that of ABMT; 2) the risk of relapse is similar with either preparatory regimen; 3) patients with fewer prior relapses enjoyed superior overall and event-free survival as well as fewer relapses; and 4) there were no significant differences in the two preparatory regimens when combined with PBPCT in relapsed or refractory NHL.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/patología , Linfoma no Hodgkin/terapia , Adolescente , Adulto , Eliminación de Componentes Sanguíneos/métodos , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante Autólogo , Resultado del Tratamiento

RESUMEN

STUDY OBJECTIVE: To identify clinical variables of pneumonia in children with acute leukemia that predicted respiratory failure and mortality. DESIGN: A retrospective chart review of children with acute leukemia admitted to the hospital with the diagnosis of pneumonia or ARDS from March 1991 to April 1994. SETTING: Lucile Salter Packard Children's Hospital at Stanford, a 168-bed teaching hospital and regional tertiary referral center for children in northern California. PATIENTS: During this study period, 20% of the 174 admissions of children with acute leukemia had pneumonia at the time of admission or during the course of the hospitalization for a total of 36 admissions. The mean age of these children was 9.2 +/- 1.1 years. RESULTS: Eleven percent of the children with pulmonary infiltrates in one quadrant on the chest x-ray film at the onset of pneumonia and 53% of the children with pulmonary infiltrates in more than one quadrant at the onset of pneumonia died. Fifteen percent of the children without sepsis at the onset of pneumonia and 70% of the children with sepsis at onset died. Eighteen percent of the children without shock at the onset of pneumonia and 75% of the children with shock at the onset died. None of the children died who required < or = 3L/min of O2 to maintain SO2 > or = 95%, but 79% of the children who required > 3L/min O2 died. Using the criteria "> 3 L/min O2 by nasal cannula to maintain SO2 > or = 95%" to identify the nonsurvivors had a sensitivity of 100% and specificity of 88%. This specificity was not increased by combining the criteria "O2 requirements at any time" and "the extent of pulmonary infiltrates at the onset of pneumonia." All children who required mechanical ventilatory support for respiratory failure had previously received > 3 L/min O2 by nasal cannula to maintain SO2 > or = 95% for 37.8 +/- 12.9 h (range 3 to 96 h). Nine of the 10 children in our study who received mechanical ventilation died. CONCLUSION: In children with acute leukemia and pneumonia, the amount of O2 required to maintain SO2 > or = 95% may identify those who are likely to develop respiratory failure hours before mechanical ventilatory support is needed. The ability to identify children at risk for respiratory failure is not increased by combining the risk factors "oxygen requirements" and "extent of pulmonary infiltrates at the onset of pneumonia". Finally, only 10% of the children who required mechanical ventilatory support survived.

Asunto(s)

Neumonía/complicaciones , Neumonía/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Trasplante de Médula Ósea , Niño , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Insuficiencia Respiratoria/complicaciones , Insuficiencia Respiratoria/mortalidad , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y Especificidad , Tasa de Supervivencia

RESUMEN

OBJECTIVE: To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS: Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS: In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS: The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases.

Asunto(s)

Neoplasias Pulmonares/genética , Pulmón/patología , Blastoma Pulmonar/genética , Adulto , Niño , Preescolar , Cromosomas Humanos Par 11 , Exones , Genes Supresores de Tumor , Humanos , Cariotipificación , Neoplasias Pulmonares/patología , Linaje , Blastoma Pulmonar/patología

RESUMEN

Ninety-four consecutive patients with chronic myelogenous leukemia in first clinical chronic phase, median age of 34.0 years (range, 6.8 to 52.4 years), with a histocompatible sibling donor, were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation (BMT). The median time from diagnosis to BMT was 7.0 months (range, 2.3 to 72.0 months). Sixty patients were treated before BMT with hydroxyurea alone, four patients with busulfan alone, one patient with interferon alone, and the other 29 patients were treated with various combinations of these drugs. Cumulative probabilities of overall survival, event-free survival, and relapse at 5 years were 73%, 64%, and 14%, respectively. The median follow-up time for surviving patients was 38 months, ranging from 12 to 88 months. By stepwise Cox regression analysis, significant prognostic variables were age at transplant, acute graft-versus-host disease > or = grade II, cytomegalovirus-associated interstitial pneumonitis, and years from diagnosis to BMT.

Asunto(s)

Trasplante de Médula Ósea/inmunología , Etopósido/uso terapéutico , Terapia de Inmunosupresión/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Irradiación Corporal Total , Adolescente , Adulto , Trasplante de Médula Ósea/mortalidad , Causas de Muerte , Niño , Aberraciones Cromosómicas , Trastornos de los Cromosomas , Ciclosporina/uso terapéutico , Citogenética , Quimioterapia Combinada , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Metotrexato/uso terapéutico , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Recurrencia , Tasa de Supervivencia

RESUMEN

In 1983, we began a series of clinical trials with the goal of reducing the relapse rate following allogeneic BMT for hematologic malignancies. Because of its anti-leukemic activity, the drug VP-16 was chosen and combined with total body irradiation (TBI). The first series (trial I) consisted of patients who had advanced leukemia. This trial showed a relapse rate of 32% and a disease-free survival rate of 43%. Thereafter, this regimen was tested in a randomized trial (trial II) under the auspices of the Southwest Oncology Group (SWOG study 8612). The FTBI/VP-16 regimen was compared with the combination of busulfan and cyclophosphamide (BU/CY). A recent analysis indicates a disease-free advantage for patients prepared with FTBI/VP-16; however this difference is not statistically significant. In another trial (trial III), patients in their first remission of leukemia were prepared with the FTBI/VP-16 regimen and long-term disease-free survival was found to be 60-70% with a relapse rate of approximately 10%. These results compare favorably with data obtained with alternative preparatory regimens. The FTBI/VP-16 regimen is currently being compared to the 'standard' regimen, FTBI/CY, in a prospective trial (trial IV). Since the regimen-related toxicity has been relatively low, we have added one dose of CY 60 mg/kg to the FTBI/VP-16 combination. This regimen (trial V) is currently being tested in patients with advanced leukemia. The preliminary results of this ongoing trial indicate further improvement in disease-free survival through a reduction of the post-transplant relapse rate.

Asunto(s)

Trasplante de Médula Ósea/métodos , Etopósido/uso terapéutico , Leucemia/terapia , Linfoma/terapia , Análisis Actuarial , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Terapia Combinada , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Leucemia/tratamiento farmacológico , Leucemia/mortalidad , Linfoma/tratamiento farmacológico , Linfoma/mortalidad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Resultado del Tratamiento , Irradiación Corporal Total