Síndrome hemofagocítico: expresión de diversas entidades nosológicas / Haemophagocytic syndrome: A common pathogenic mechanism of various aetiologies

Introducción: El síndrome hemofagocítico (SH) se caracteriza por una activación y proliferación incontrolada de histiocitos y linfocitos T, que produce un estado de hipercitocinemia. Hay 2 formas: primaria y secundaria. Objetivo: Análisis de los pacientes diagnosticados de SH según los criterios diagnósticos de los protocolos HLH (hemophagocytic lymphohistiocytosis ‘linfohistiocitosis hemofagocítica’)-94 y HLH-2004. Pacientes y métodos: Se revisó de forma retrospectiva la historia clínica de los pacientes diagnosticados de SH, se analizaron los criterios diagnósticos, la forma de presentación, la etiología, el tratamiento administrado y el curso evolutivo. Resultados: Se diagnosticó a 22 pacientes: 6 con formas familiares, 11 con formas asociadas a infección, 3 con formas asociadas a neoplasia y 2 con síndromes de activación macrofágica (estos pacientes con artritis idiopática juvenil y enfermedad de Crohn [EC]). En el 83,3% de los casos de linfohistiocitosis hemofagocítica familiar (LHF) la edad al diagnóstico fue inferior al año de vida. En un paciente adolescente se diagnosticó una forma primaria de la enfermedad (mutación del gen MUNC13-4). Las manifestaciones clínicas fueron fiebre (100%), hepatoesplenomegalia (85%), adenopatías (31%), palidez (21%), exantema (14%) y alteraciones neurológicas (14%); los hallazgos de laboratorio fueron citopenia (100%), hipertrigliceridemia (93%), hiperferritinemia (86%), elevación de las enzimas hepáticas (78%) e hipofibrinogenemia (40%). Se encontró una reducción de actividad de los linfocitos citolíticos naturales en el 100% de los casos. Se observó hemofagocitosis en la médula ósea en 20 pacientes. En 2 pacientes se realizó una biopsia hepática y ganglionar que demostró hemofagocitosis. Evolución: de los 22 pacientes diagnosticados de SH, 10 pacientes recibieron tratamiento según los protocolos HLH-94 y HLH-2004: 6 con LHF, 3 con formas secundarias al virus de Epstein-Barr y uno a la EC. De éstos, 6 pacientes recibieron un trasplante de progenitores hematopoyéticos (TPH), con evolución favorable en 2 de los casos con LHF. Los otros 12 pacientes con formas secundarias recibieron tratamiento etiológico, con buena evolución en el 83,3%. Conclusiones: Las formas familiares de SH se diagnostican generalmente antes de los 2 años de edad, aunque se presentan formas primarias en edades más avanzadas. El tratamiento quimioterapéutico e inmunosupresor y el TPH constituyen la base del tratamiento de las formas familiares. Las formas secundarias deben recibir tratamiento etiológico y, si la evolución no es favorable, tratamiento quimioterapéutico e inmunosupresor (AU)

Introduction: Haemophagocytic syndrome (HPS) is a rare syndrome characterised by the uncontrolled activation and proliferation of histiocytes and T cells, leading to a cytokines overproduction. There are two forms of HPS: primary and secondary. Objective: To analyse patients diagnosed with HPS at the Oncohaematology Department, using HLH-94 and 2004 protocol diagnostic criteria. Materials and methods: Retrospective study of clinical files of patients diagnosed with HPS, analysing the following features: diagnostic criteria, variability in clinical presentation, aetiology, treatment and outcome. Results: Twenty-two patients were diagnosed with HPS: 6 familial haemophagocytic lymphohistiocytosis (FHL), 11 HPS with evidence of infection, 3 HPS associated with malignant disease and 2 macrophage activation syndrome (MAS) in patients with Crohn's disease and Juvenile Idiopathic Arthritis. The onset of FHL was within 1 year of age in 83.3%, except for 1 patient who was adolescent (MUNC13-4 mutations). Symptoms: All patients (100%) had fever at diagnosis, 18 (85%) hepatosplenomegaly, 7 (31%) lymphadenopathy, 5 (21%) pallor, 3 (14%) rash and 3 (14%) neurological symptoms. Laboratory analysis: all patients (100%) had cytopenias at diagnosis, 20 (90.9%) hypertriglyceridaemia, 19 (86%) hyperferritinaemia, 17 (77%) elevated serum liver enzymes, and 9 (40%) hypofibrinogenaemia. Decreased or absent NK-cell activity was detected in all patients (100%). Haemophagocytosis was found more frequently in bone marrow; however, liver or lymph node biopsies were required in two patients to demonstrate this. Outcome: Of the ten patients (6 FHL, 3 Epstein-Barr virus-associated HPS and 1 MAS) treated with HLH-94 and 2004 protocols, six received a stem-cell transplant; of these, 2 with FHL had a favourable outcome. The remaining 12 patients received aetiological/supportive therapy, with complete remission in 83.3%. Conclusions: The diagnosis of FHL should be made before the age of 2 years. Advances in genetic studies allow the detection of early and late forms of FHL. Immunochemotherapy and stem-cell transplantation constitute the treatment of FHL and aetiological/supportive therapy of acquired haemophagocytic lymphohistiocytosis, except in severe forms (AU)

[Haemophagocytic syndrome: A common pathogenic mechanism of various aetiologies]. / Síndrome hemofagocítico: expresión de diversas entidades nosológicas.

INTRODUCTION: Haemophagocytic syndrome (HPS) is a rare syndrome characterised by the uncontrolled activation and proliferation of histiocytes and T cells, leading to a cytokines overproduction. There are two forms of HPS: primary and secondary. OBJECTIVE: To analyse patients diagnosed with HPS at the Oncohaematology Department, using HLH-94 and 2004 protocol diagnostic criteria. MATERIALS AND METHODS: Retrospective study of clinical files of patients diagnosed with HPS, analysing the following features: diagnostic criteria, variability in clinical presentation, aetiology, treatment and outcome. RESULTS: Twenty-two patients were diagnosed with HPS: 6 familial haemophagocytic lymphohistiocytosis (FHL), 11 HPS with evidence of infection, 3 HPS associated with malignant disease and 2 macrophage activation syndrome (MAS) in patients with Crohn's disease and Juvenile Idiopathic Arthritis. The onset of FHL was within 1 year of age in 83.3%, except for 1 patient who was adolescent (MUNC13-4 mutations). SYMPTOMS: All patients (100%) had fever at diagnosis, 18 (85%) hepatosplenomegaly, 7 (31%) lymphadenopathy, 5 (21%) pallor, 3 (14%) rash and 3 (14%) neurological symptoms. LABORATORY ANALYSIS: all patients (100%) had cytopenias at diagnosis, 20 (90.9%) hypertriglyceridaemia, 19 (86%) hyperferritinaemia, 17 (77%) elevated serum liver enzymes, and 9 (40%) hypofibrinogenaemia. Decreased or absent NK-cell activity was detected in all patients (100%). Haemophagocytosis was found more frequently in bone marrow; however, liver or lymph node biopsies were required in two patients to demonstrate this. OUTCOME: Of the ten patients (6 FHL, 3 Epstein-Barr virus-associated HPS and 1 MAS) treated with HLH-94 and 2004 protocols, six received a stem-cell transplant; of these, 2 with FHL had a favourable outcome. The remaining 12 patients received aetiological/supportive therapy, with complete remission in 83.3%. CONCLUSIONS: The diagnosis of FHL should be made before the age of 2 years. Advances in genetic studies allow the detection of early and late forms of FHL. Immunochemotherapy and stem-cell transplantation constitute the treatment of FHL and aetiological/supportive therapy of acquired haemophagocytic lymphohistiocytosis, except in severe forms.

[Minimal residual disease in acute lymphoblastic leukemia: a new concept of complete remission]. / Leucemia mínima residual: nuevo concepto de remisión completa.

INTRODUCTION: Early response to induction treatment is one of the most important prognostic factors in children with acute lymphoblastic leukemia (ALL). Cytological remission is currently achieved in 95-98 % of these patients, although a significant proportion will later relapse. More sensitive techniques are required to measure residual leukemia and establish a new definition of complete remission. OBJECTIVE: To identify minimal residual disease (MRD) by immunological techniques and define its prognostic impact in children with ALL. METHODS: MRD was studied by flow cytometry in 53 children diagnosed in our department between June 1999 and April 2003 and treated using the Pethema protocols. All the children achieved complete cytological remission (< 5 %) with the induction treatment and had at least one useful phenotype for follow-up: 11 % were T phenotype, one was biphenotypic and the remainder were B cell leukemias. Bone marrow samples were analyzed post-induction, post-consolidation, after 6 and 11 months of maintenance treatment, at the end of treatment, and 3 months later. The positivity threshold was set at 0.01 % and the sensitivity of the technique was 1 x 10(-4)-1 x 10(-5). RESULTS: A total of 199 samples were analyzed. Thirty-seven percent of the post-induction and 20 % of the post-consolidation samples analyzed were MRD-positive. Elimination was slower in patients with a T phenotype and in high-risk patients according to the traditional classification. After a median follow-up of 26 months, event free survival (EFS) in the group as a whole was 92 %. The EFS rate in the patients who were MRD-positive post-induction was 79 %. None of the patients who were MRD-negative post-induction has developed recurrence. CONCLUSION: Study of MRD is essential and should be included in all current treatment protocols for children with ALL. Its usefulness derives from the prognostic impact of the response to induction treatment. Continued sequential monitoring may predict recurrence before the onset of clinical or hematologic manifestations.

Leucemia mínima residual: nuevo concepto de remisión completa / Minimal residual disease in acute lymphoblastic leukemia: a new concept of complete remission

Introducción: La respuesta precoz al tratamiento de inducción es uno de los factores pronósticos más importantes en niños afectados de leucemia linfoblástica aguda (LLA). Actualmente se consigue la remisión citológica en el 95-98 % de estos pacientes; sin embargo, un porcentaje importante recaerá posteriormente. Es preciso utilizar técnicas más sensibles para medir la leucemia residual y establecer un nuevo concepto de remisión completa. Objetivo: Identificar por técnicas inmunológicas la enfermedad mínima residual (EMR) y conocer su impacto pronóstico en niños afectados de LLA. Métodos: Estudiamos la EMR por citometría de flujo en 53 niños diagnosticados en nuestro servicio desde junio de 1999 hasta abril de 2003 y tratados según protocolos del grupo Pethema. Todos habían conseguido la remisión citológica (< 5 %) con el tratamiento de inducción y tenían al menos un fenotipo útil para seguimiento. El 11 % eran de fenotipo T, 1 bifenotípica y el resto eran leucemias tipo B. Se analizaron muestras de médula ósea postinducción, posconsolidación, a 6 y 11 meses de mantenimiento, al final del tratamiento y 3 meses después. Se colocó el umbral de positividad en 0,01 %, siendo la sensibilidad de la técnica de 1 x 10­4-1 x 10­5. Resultados: Se analizaron un total de 199 muestras. El 37 % de las muestras analizadas postinducción y el 20 % posconsolidación eran EMR1. La eliminación fue más lenta en los pacientes de fenotipo T y en los de alto riesgo según la clasificación tradicional. Con una mediana de seguimiento de 26 meses, la supervivencia libre de enfermedad (SLE) del grupo completo fue del 92 %. Los pacientes con una EMR1 postinducción tuvieron una tasa de SLE del 79 %. Ningún paciente con EMR-postinducción ha presentado recidiva. Conclusión: El estudio de la EMR es imprescindible y debe estar incluida en todos los protocolos de tratamiento actuales para niños con LLA. Su utilidad radica en el impacto pronóstico de la respuesta al tratamiento de inducción. La monitorización secuencial posterior puede predecir recaídas antes de que aparezcan manifestaciones clínicas o hematológicas

Introduction: Early response to induction treatment is one of the most important prognostic factors in children with acute lymphoblastic leukemia (ALL). Cytological remission is currently achieved in 95-98 % of these patients, although a significant proportion will later relapse. More sensitive techniques are required to measure residual leukemia and establish a new definition of complete remission. Objective: To identify minimal residual disease (MRD) by immunological techniques and define its prognostic impact in children with ALL. Methods: MRD was studied by flow cytometry in 53 children diagnosed in our department between June 1999 and April 2003 and treated using the Pethema protocols. All the children achieved complete cytological remission (< 5 %) with the induction treatment and had at least one useful phenotype for follow-up: 11 % were T phenotype, one was biphenotypic and the remainder were B cell leukemias. Bone marrow samples were analyzed post-induction, post-consolidation, after 6 and 11 months of maintenance treatment, at the end of treatment, and 3 months later. The positivity threshold was set at 0.01 % and the sensitivity of the technique was 1 x 10­4-1 x 10­5. Results: A total of 199 samples were analyzed. Thirty-seven percent of the post-induction and 20 % of the post-consolidation samples analyzed were MRD-positive. Elimination was slower in patients with a T phenotype and in high-risk patients according to the traditional classification. After a median follow-up of 26 months, event free survival (EFS) in the group as a whole was 92 %. The EFS rate in the patients who were MRD-positive post-induction was 79 %. None of the patients who were MRD-negative post-induction has developed recurrence. Conclusion: Study of MRD is essential and should be included in all current treatment protocols for children with ALL. Its usefulness derives from the prognostic impact of the response to induction treatment. Continued sequential monitoring may predict recurrence before the onset of clinical or hematologic manifestations

[Transient neonatal myeloproliferative disorder in the absence of Down syndrome]. / Síndrome mieloproliferativo transitorio neonatal en ausencia de síndrome de Down.

Transient neonatal leukemia or transient neonatal myeloproliferative disorder is commonly associated with Down syndrome. It usually resolves spontaneously in 4-5 months. However, 25 % of patients will subsequently develop acute megakaryoblastic leukemia or myelodysplastic syndrome. It has seldom been described without constitutional anomalies and is even less frequent in twins. We present three phenotypically normal patients with this disorder. One of them was diagnosed because he presented blueberry muffin syndrome. Diagnosis was guided by pathological examination of the skin lesions. The other two patients were monochorionic triplets. Their bichorionic sister presented no hematological disorders. Constitutional chromosomal abnormalities were ruled out in all three patients. They received support treatment only without chemotherapy. The clinical course was favorable with disappearance of marrow and peripheral blastosis in 4-5 months. Follow-up of 18 and 19 months has not revealed any hematological disorders. Caution must be exercised before initiating chemotherapy in these patients. We discuss the differential diagnosis with congenital leukemia and the prognostic and therapeutic implications that this entails.

Síndrome mieloproliferativo transitorio neonatal en ausencia de síndrome de Down / Transient neonatal myeloproliferative disorder inthe absence of Down syndrome

El síndrome mieloproliferativo transitorio o leucemia transitoria neonatal es una entidad que suele asociarse a pacientes afectados de síndrome de Down. Se resuelve de manera espontánea en 4 o 5 meses, salvo en el 25 por ciento de los casos en que puede desarrollarse posteriormente una leucemia megacarioblástica aguda, o bien un síndrome mielodisplásico. Rara vez se ha descrito sin anomalías constitucionales y aún menos en gemelos. Se presentan 3 pacientes, fenotípicamente normales, afectados por esta enfermedad. Uno de ellos fue diagnosticado por presentar un síndrome de "blueberry muffin baby". El estudio anatomopatológico de las lesiones cutáneas orientó el diagnóstico. Los otros eran dos trillizas monocoriales. Su hermana bicorial con las dos anteriores no presentó alteraciones hematológicas. En todos se descartó la cromosomopatía constitucional. Sólo recibieron tratamiento de soporte sin quimioterapia. La evolución fue favorable, desapareciendo la blastosis medular y periférica en 4 o 5 meses. Con un período de seguimiento de 18 y 19 meses no han presentado nueva patología hematológica. Se debe ser cauto antes de iniciar la quimioterapia en estos pacientes.Se comenta el diagnóstico diferencial con la leucemia congénita y las implicaciones pronósticas y terapéuticas que conlleva (AU)

[Granulocyte colony-stimulating factor in the newborn neutropenic patient]. / Factor estimulante de colonias granulocíticas en el recién nacido neutropénico.

OBJECTIVE: To assess the therapeutic effect of G-CSF in newborns with neutropenia. METHODS: Newborn with evidence of both peripheral neutropenia and decreased granulocytic precursors in tibial bone marrow aspirate were included in the study. G-CSF was perfused intravenously over 2 hours at dose of 10 micrograms/kg/day, during 4-8 days. CBC were obtained immediately before each dose of G-CSF. RESULTS: Neutropenia followed neonatal sepsis in four cases and maternal pre-eclampsia in three. Prior to treatment, peripheral blood granulocyte (PMNL) counts ranged from 420 to 1,073/mm3. Once G-CSF infusion was started, counts returned to normal within 24-48 hours. No adverse effects related to G-CSF administration were noticed. CONCLUSIONS: G-CSF induces a significant increase in peripheral PMNL counts in newborn with neutropenia, in the absence of significant toxic effects. Our date suggest a potential role for G-CSF in the prophylaxis and treatment of sepsis in the neutropenic newborn, although widespread recommendation must await further, controlled studies.

[Evolution of the treatment of acute nonlymphoblastic leukemias in children (1968-1990)]. / Evolución del tratamiento de las leucemias agudas no linfoblásticas en el niño (1968-1990).

Changes in treatment of ANLL in children over 23 years (1968-90) and advances made in the last ten years in a pediatric hematological unit are reported herein. Of 124 patients under 15 years of age, 18 of whom were infants, 118 were evaluable. Of these, 58 were treated before 1980 and, although complete remission (CR) was attained in 75%, the median duration was lower than 12 months and no patient survived in CR more than 6 years. From 1981 to 1987, 40 patients received one or two induction treatments followed by three consolidations and then blocks of sequential intensive chemotherapy for 12-15 months. CR was attained in 87.5% and event-free survival (EFS) was 22.5% at 8 years: 14% for those treated from 1981 to 1983 and 33% for those included in the ANLL-84 protocol. In 1988, a post-remission protocol with intensification therapy (two high-dose ARA-C treatments combined with mitoxantrone in the first and amsacrine in the second) followed by allogeneic or autologous bone marrow transplant (BMT) was initiated. Of 20 patients included, 17 reached CR (85%) and 16 underwent BMT. EFS of the 20 patients was 65% at 2 years and post-BMT relapse-free survival was 75%. These results are compared with those obtained separately with present intensive chemotherapy protocols and with BMT and it is concluded that intensification treatment followed by BMT (allogeneic or autologous) might constitute an advance in the treatment of children with ANLL.

[Intensification chemotherapy followed by allogenieic and autologous bone marrow transplantation in acute non-lymphoblastic leukemia in children]. / Quimioterapia de intensificación seguida de trasplante de médula ósea alogénico o autólogo en leucemias agudas no linfoblásticas en niños.

UNLABELLED: Both intensification therapies with high-doses ARA-C and bone marrow transplant, allogeneic (BMT) or autologous (ABMT), have proved effective in relapse prevention in ANLL. The present study combines both treatments. METHODS. Remission induction treatment was DAE combination. The first intensification consisted of HD ARA-C and mitoxantrone and the second HD ARA-C and AMSA. CNS prophylaxis consisted of 6 doses of i.t. ARA-C and MTX. Later, patients in remission with HLA-compatible donor received BMT and those without it, ABMT with "ex vivo" treatment of the bone marrow with ASTA-Z. Pre-BMT treatment was the same in both cases: fractionated total body irradiation (TBI) and cyclophosphamide in patients over 3 years of age; in patients under 3 busulfan was given instead of TBI. PATIENTS. Between April 88 and March 90, 18 patients (age 3 months to 14 years) were included. FAB subtypes were M1 + M2: 4; M3: 2; M4: 4; M5: 5; M6: 1; M7: 2. Two patients died of cranial haemorrhage before the 10th day, 15 achieved complete remission (CR) after one or two induction treatments and 1 only attained CR after the first intensification. RESULTS: 1 patient with M7 relapsed after the 2nd intensification. Of the remaining 15, five received BMT and ten ABMT. Average interval between CR and transplant was 4 months (3 to 8). Of the 5 with BMT, one died from progressive obliterating bronchiolitis at 9 months and the other four continued in CR for 6 to 28 months. Of the 10 with ABMT none died from complications, 2 suffered early relapse and 8 continued in CR for 6 to 28 months.(ABSTRACT TRUNCATED AT 250 WORDS)