[Twenty years of treating childhood acute lymphoblastic leukemia]. / Veinte años de experiencia en el tratamiento de la leucemia linfoblástica aguda.

BACKGROUND: Conventional prognostic factors for relapse in patients with acute lymphoblastic leukemia (ALL) are the main basis of risk-stratified treatments. OBJECTIVES: To analyze conventional risk factors for relapse and design a predictive model for relapse in our series, after 20 years of experience in treating ALL. PATIENTS AND METHOD: We performed a multivariate analysis of conventional prognostic factors in the treatment of ALL in our unit and compared them with the risk groups in the Berlin-Frankfurt-Münster (BFM-ALL) treatment protocols. RESULTS: Between 1984 and 2004, 232 children were diagnosed with ALL and treated according to the different versions of the BFM protocols (BFM83, BFM86, BFM90 and BFM95) at the Hospital Niño Jesús, Madrid, Spain. The event-free survival for all patients was 79.4 % (95 % CI: 72.7-85.4). Overall survival among patients who relapsed was 10.72 % (95 % CI: 6-27.3). The only significant prognostic factor for relapse identified by multivariate analysis was leukocyte [white blood cell (WBC)] count higher than 80,000/ml at diagnosis (hazard ratio [HR]: 4.63; 95 % CI: 1.61-13.3; p 5 0,004). The sensitivity and specificity of WBC in predicting relapses were 31.4 % and 87.5 %, respectively. The sensitivity and specificity of BFM risk group stratification in predicting relapses were 25 and 85.9 respectively. CONCLUSIONS: A leukocyte count at diagnosis higher than 80,000/ml and BFM risk-stratified treatment have insufficient sensitivity and specificity to identify relapses.

Veinte años de experiencia en el tratamiento de la leucemia linfoblástica aguda / Twenty years of treating childhood acute lymphoblastic leukemia

Antecedentes Los factores pronósticos en el tratamiento de la leucemia linfoblástica aguda (LLA) son la base del tratamiento adaptado al grupo de riesgo. Objetivos Analizar los factores de riesgo convencionales y establecer un modelo predictivo de recaída en nuestra serie, tras 20 años de experiencia en el tratamiento de la LLA. Pacientes y método Realizamos un análisis multivariante de los factores pronósticos convencionales en el tratamiento de la LLA y los comparamos con los grupos de riesgo del protocolo de tratamiento Berlín-Frankfurt-Münster (LLA-BFM), en nuestra unidad. Resultados Entre 1984 y 2004, un total de 232 niños fueron diagnosticados de LLA y tratados siguiendo el protocolo BFM en sus diferentes versiones (BFM83, BFM86, BFM90 y BFM95). La supervivencia libre de episodios de la serie fue de 79,4 % (IC 95 %: 72,7-85,4). La supervivencia global de los pacientes que recayeron fue de 10,72 % (IC 95 %: 6-27,3). La única variable predictora en el análisis multivariante fue el número de leucocitos al diagnóstico mayor de 80.000/ml (hazard ratio [HR]: 4,63; IC 95 %: 1,61-13,3; p 5 0,004). La sensibilidad y especificidad del número de leucocitos al diagnóstico mayor de 80.000/ml para predecir la recaída fue en nuestra serie de 31,4 y 87,5, respectivamente. La sensibilidad y especificidad de los grupos de riesgo BFM para predecir la recaída fue de 25 y 85,9, respectivamente. Conclusiones El número de leucocitos al diagnóstico mayor de 80.000/ml o los grupos de tratamiento adaptados al riesgo según las variables convencionales no tienen suficiente sensibilidad y especificidad para identificar las recaídas

Background Conventional prognostic factors for relapse in patients with acute lymphoblastic leukemia (ALL) are the main basis of risk-stratified treatments. Objectives To analyze conventional risk factors for relapse and design a predictive model for relapse in our series, after 20 years of experience in treating ALL. Patients and method We performed a multivariate analysis of conventional prognostic factors in the treatment of ALL in our unit and compared them with the risk groups in the Berlin-Frankfurt-Münster (BFM-ALL) treatment protocols. Results Between 1984 and 2004, 232 children were diagnosed with ALL and treated according to the different versions of the BFM protocols (BFM83, BFM86, BFM90 and BFM95) at the Hospital Niño Jesús, Madrid, Spain. The event-free survival for all patients was 79.4 % (95 % CI: 72.7-85.4). Overall survival among patients who relapsed was 10.72 % (95 % CI: 6-27.3). The only significant prognostic factor for relapse identified by multivariate analysis was leukocyte [white blood cell (WBC)] count higher than 80,000/ml at diagnosis (hazard ratio [HR]: 4.63; 95 % CI: 1.61-13.3; p 5 0,004). The sensitivity and specificity of WBC in predicting relapses were 31.4 % and 87.5 %, respectively. The sensitivity and specificity of BFM risk group stratification in predicting relapses were 25 and 85.9 respectively. Conclusions A leukocyte count at diagnosis higher than 80,000/ml and BFM risk-stratified treatment have insufficient sensitivity and specificity to identify relapses

[High-dose chemotherapy with autologous stem cell rescue in children with high-risk and recurrent brain tumors]. / Trasplante autólogo con progenitores hematopoyéticos de sangre periférica en niños con tumores del sistema nervioso central de alto riesgo.

BACKGROUND: In the last few years, survival in children with central nervous system (CNS) tumors has slightly improved, especially in children with tumors such as medulloblastoma and those in which complete surgical resection is achieved. However, outcome remains poor in patients with incomplete surgical resection, neuroaxial dissemination, metastatic or recurrent tumors and in very young children. OBJECTIVES: To improve prognosis in patients with high-risk and recurrent tumors, new therapeutic strategies such as high-dose chemotherapy with autologous stem cell rescue (ASCR) have been developed. METHODS: We retrospectively studied patients with high-risk and recurrent CNS tumors who underwent ASCR between September 1995 and December 2002 in our unit. RESULTS: Thirty-five patients underwent ASCR. Seven patients died of treatment-related toxicities (20 %). Thirteen (37 %) are event-free survivors at a median post-ASCR follow-up of 18 months (range: 5-63 months). The 2-year Kaplan-Meier estimates of event-free survival was 37.64 +/- 8.7 % in all patients, 57 +/- 15 % in the group of patients with high-risk medulloblastoma/supratentorial primitive neuroectodermal tumor (stPNET) and 71.43 +/- 17 % in patients aged less than 4 years with medulloblastoma/stPNET. CONCLUSIONS: In our experience, ASCR may be effective in the treatment of malignant tumors of the central nervous system in patients with controlled disease, in certain histologic groups and chemosensitive tumors (medulloblastoma, malignant astrocytoma), as well as in very young children in whom cranial radiotherapy is contraindicated.

Trasplante autólogo con progenitores hematopoyéticos de sangre periférica en niños con tumores del sistema nervioso central de alto riesgo / High-dose chemotherapy with autologous stem cell rescue in children with high-risk and recurrent brain tumors

Antecedentes. En los últimos años ha mejorado discretamente la supervivencia de los niños con tumores del sistema nervioso central (SNC). Especialmente en tumores como el meduloblastoma y en aquellos en los que se consigue una resección quirúrgica completa. En cambio, los pacientes con resecciones quirúrgicas incompletas, tumores diseminados por el neuroeje, metastásicos, recurrentes o en los pacientes de menor edad, el pronóstico resulta muy pobre. Objetivos. Con intención de mejorar el pronóstico de los pacientes de alto riesgo y con enfermedad recurrente, se han desarrollado nuevas estrategias terapéuticas como el trasplante autólogo de progenitores hematopoyéticos (TAPH). Métodos. Revisión retrospectiva de los pacientes con tumores de alto riesgo del SNC y recurrentes sometidos a TAPH entre los meses de septiembre de 1995 y diciembre de 2002 en nuestra unidad. Resultados. Un total de 35 pacientes fueron trasplantados. Fallecieron 7 pacientes (20 por ciento) por toxicidad del procedimiento y 15 pacientes (42 por ciento) por enfermedad progresiva, 13 pacientes se encuentran vivos, con una mediana de seguimiento tras el trasplante de 18 meses (5-63 meses). La supervivencia libre de enfermedad (SLE) estimada mediante el método de Kaplan-Meier con una mediana de 2 años fue de 37,64 +/- 8,7 por ciento, en todos los pacientes; de 57 +/- 15 por ciento en los pacientes con meduloblastoma/tumor primitivo neuroectodérmico supratentorial (MB/stPNET) de alto riesgo, y de 71,43 +/- 17 por ciento en los pacientes con MB/stPNET menores de 4 años. Conclusiones. En nuestra experiencia el TAPH podría ser efectivo en el tratamiento de los tumores malignos del SNC en pacientes con enfermedad controlada y en determinados grupos histológicos, tumores quimiosensibles (meduloblastoma, astrocitoma anaplásico), así como en los niños de menor edad donde la radioterapia craneal está contraindicada (AU)

Alteraciones en la función gonadalen varones pospuberales supervivientesde leucemia linfoblástica aguda y enfermedad de Hodgkin / Alterations in gonadal function in post-pubertal male survivors of acute lymphoblastic leukemia and Hodgkin's disease

OBJETIVO: Estudiar la función gonadal en varones supervivientes de leucemia linfoblástica aguda (LLA) y enfermedad de Hodgkin (EH). PACIENTES Y MÉTODOS: Se estudiaron 13 varones pospuberales (estadio V de Tanner), 9 con LLA y 4 con EH, que habían recibido poliquimioterapia durante el período prepuberal. El grupo control lo constituyeron 13 varones voluntarios de edad similar y de desarrollo puberal completo. Se determinó: tamaño testicular, espermiograma, valores séricos de hormonas folículo estimulante (FSH) y luteinizante (LH), basales y tras estímulo con GnRH (hormona liberadora de gonadotropinas), y testosterona basal (T1). Se consideró que existía daño del epitelio germinal cuando se encontró, al menos, uno de los siguientes criterios: a) oligospermia/azoospermia; b) aumento de FSH basal o tras GnRH, o c) reducción del volumen testicular. Se consideró que existía lesión de las células de Leydig cuando los valores plasmásticos de testosterona basal se encontraron disminuidos, o los valores de LH, basales o tras estímulo, aumentados. RESULTADOS: Los pacientes diagnosticados de EH presentaron una clara alteración de la función germinal y, en menor medida, de la función de las células de Leydig, con diferencias significativas respecto al grupo control (p < 0,001) en: pico de FSH (19,7 ñ 18 frente a 4,8 ñ 1,8 mU/ml), pico de LH (49,2 ñ 31 frente a 33,4 ñ 10,0 mU/ml), testosterona (4,1 ñ 0,6 ng/ml frente a 5,9 ñ 0,3 ng/ml) y volumen testicular (16,6 ñ 2,8 frente a 22,5 ñ 2,4 ml). De los 4 pacientes con EH, tres presentaron azoospermia y uno oligoespermia. Los pacientes supervivientes de LLA no presentaron diferencias significativas en ninguno de los parámetros bioquímicos y clínicos con el grupo control, si bien, de los 9 pacientes estudiados, dos presentaron oligospermia. CONCLUSIÓN: Los protocolos quimioterápicos empleados en el tratamiento de la EH y la LLA producen una elevada incidencia de daño germinal y de alteración subclínica de las células de Leydig en los varones con EH; mientras que en los pacientes diagnosticados de LLA se encuentra sólo una afectación leve de la línea germinal. El estado prepuberal no protege los testículos del efecto nocivo de la quimioterapia (AU)

[The treatment results in children diagnosed with non-Hodgkin's lymphomas and acute B-cell lymphoblastic leukemias treated by the BFM protocols. The report of the POGM (Pediatric Oncology Group of Madrid)]. / Resultados del tratamiento de niños diagnosticados de linfomas no Hodgkin y leucemias linfoblásticas agudas de células B tratados con protocolos BFM. Informe del GOPM (Grupo de Oncología Pediátrica de Madrid).

OBJECTIVE: The purpose of this study was to reproduce the results obtained by the "BFM Group" in children with NHL and B-ALL treated with BFM 86 and 90 protocols. PATIENTS AND METHODS: From April 1987 until January 1997, we have treated a total of 82 children, 22 with non-B NHL, 49 B-NHL and 11 B-ALL. Forty-four of them were treated according to BFM 86 and 38 according to BFM 90 protocols. RESULTS: Ninety-four percent of the patients achieved complete remission (CR) and 15% of these relapsed, 12% of the cases of B NHL/ALL and 23% of the non-B NHL. The 5 year overall survival (Kaplan Meier) was 81% for the B NHL/ALL it was 83% and for non-B NHL 77%. The event-free survival was 75% for B-NHL, stages I and II it was 80% and stages II and IV 78%, for B-ALL 72% and for non-B NHL 68%. The median follow-up time was 50 months (12-106). CONCLUSIONS: Treatment of NHL and B-ALL with BFM protocols is an effective therapeutic choice, with reproduction of the results of the "BFM group" being feasible.

[The results of treatment by the Madrid Pediatric Oncology Group according to the BFM protocols in non-Hodgkin's B-cell lymphoma and acute B-cell lymphoblastic leukemia in pediatric patients]. / Resultados del tratamiento según protocolos BFM del linfoma no Hodgkin B y de la leucemia linfoblástica aguda de células B en pacientes pediátricos por el GOPM.

The objective of this report is to present the results of the BFM group in the treatment of 41 children with non-Hodgkin's B cell lymphoma and acute B cell lymphoblastic leukemia according to the BFM 86 and 90 protocols. Forty-one children, between 2 and 16 years of age, were treated from November 1987 to October 1993. Of these, 25 were treated with the BFM 86 protocol (18 non-Hodgkin's B cell lymphomas and 7 acute B cell lymphoblastic leukemias) and the rest with the BFM 90 protocol (15 non-Hodgkin's B cell lymphomas and 1 acute B cell lymphoblastic leukemia). Complete remission was achieved in 97.5% of the patients. A relapse occurred in 12.5% of the cases. Currently, 80.4% remain in continuous complete remission and 17% have died. The 5 year actuarial survival rate of those treated with the BFM 86 and 90 protocols was 79% and 87%, respectively, and event free survival in the same period was 76% and 87%, respectively. There was no statistically significant difference in the results obtained with the two treatment protocols.

[Control of vomiting induced by antineoplastic chemotherapy in childhood]. / Control de la emesis inducida por quimioterapia antineoplásica en la infancia.

Twenty four children aged 2 to 13 years who were to receive cancer chemotherapy were enrolled in a prospective study (before-after-trial) in order to evaluate the efficacy of systematic antiemetic prophylaxis. The regimen of three drugs (metilpednisolone 4 mg/Kg/dose/iv 2 doses; metodopamide 0.5 mg/Kg/dose/iv 4 doses; diphenydramine 1 mg/Kg/dose/iv 4 doses) was used. We found a significative reduction (P less than 0.001) in the incidence of vomiting and nauseousness duration when the antiemetic prophylaxis was used. There were very few and slight adverse effects secondary to antiemetic drugs: Sedation happened in 25% of chemotherapic cycles and hypotension without clinical repercussion in 15%. No patient had distonia. We conclude that systematical antiemetic protection should be used in children receiving chemotherapy. The association of metilpednisolone, metopramide and diphenhydramine is a safe and effective combination.

[Spinal cord compression in children with cancer]. / Síndrome de compresión medular en niños con cáncer.

Metastatic cord compression is a rare complication of malignant diseases in childhood. The most common causes are bone and soft tissue sarcomas, neuroblastoma, lymphoma and leukemia. The clinical manifestations, diagnosis, treatment and evolution of eight children with metastatic cord compression are presented. Diagnosis was based on computerized tomography that was pathological in all the cases, and confirmed by myelography in four patients. The cytological analysis of the cerebrospinal fluid was made in three patients being negative for tumoral cells in all of them. Treatment consisted on radiotherapy, chemotherapy and/or surgery depending on the tumor histology. Decompressive laminectomy was made in patients who did not show previous evidence of cancer. Functional prognosis was related with the degree of disablement at diagnosis and treatment.

[Treatment of infantile acute lymphoblastic leukemia with protocol ALL-BFM 83]. / Tratamiento de la leucemia aguda linfoblástica infantil con el protocolo ALL-BFM 83.

The outcome of 63 children with non-B acute lymphoblastic leukemia treated with ALL-BFM 83 protocol is analyzed. 95% achieved complete remission with the initial treatment. For the entire group the event free survival (EFS) was 66% (+/- 9%) at 48 months. These results were close to those obtained by the BFM group. Haematological toxicity was the main adverse effect, but there where no therapy related deaths. Persistence of more than 1,000 blast cells per microl in peripheral blood after 7th days of prednisone monotherapy, and spleen size greater than or equal to 5 cm under the costal margin, were identified as independent risk factors of high significance. The EFS in patients with poor clinical response to steroids (greater than or equal to 1,000 blast/microl at day 8) was 22% (+/- 18%), instead of 69% (+/- 12%) in those with adequate response.