RESUMEN
PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p < 0.0001), 29 (HzR 2.7, p < 0.0001), and 79 (HzR 3.5, p < 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10-2 versus 5.2 × 10-3, p < 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD > 10-4 associated with a CIR5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.
Asunto(s)
Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células Precursoras de Linfocitos B/efectos de los fármacos , Células Precursoras de Linfocitos B/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación/métodos , Lactante , Masculino , Persona de Mediana Edad , Recurrencia , Adulto JovenRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) < 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD > 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD ≥ 5% on day 29 or ≥0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citometría de Flujo/métodos , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Medición de Riesgo/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Niño , Preescolar , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence=6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting >72 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P=0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P=5.8 × 10-7; odds ratio (OR)=6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P=0.015) and had lower risk of AAP-related complications (15% vs 43%; P=0.13) compared with cases without this variant. Among 45 cases and 517 controls <10 years, the strongest associations with AAP were found for RGS6 variant rs17179470 (P=9.8 × 10-9; OR=7.3). Rs281366 is located in the ULK2 gene involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics. More than 50% of AAP cases <10 years carried one or both risk alleles.
Asunto(s)
Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Pancreatitis/etiología , Adolescente , Alelos , Antineoplásicos/uso terapéutico , Asparaginasa/uso terapéutico , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Lactante , Masculino , Oportunidad Relativa , Pancreatitis/diagnóstico , Pancreatitis/epidemiología , Fenotipo , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/genética , Índice de Severidad de la EnfermedadRESUMEN
UNLABELLED: ESSENTIALS: Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15-17 years. A TE-associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment. BACKGROUND: Thromboembolism (TE) is a major toxicity in children with acute lymphoblastic leukemia (ALL) and may have a negative impact on ALL treatment. OBJECTIVES: To examine the cumulative incidence, outcomes and risk factors associated with TE in children with leukemia. PATIENTS/METHODS: We prospectively evaluated TE in 1038 Nordic children and adolescents (≥ 1 and < 18 years) diagnosed with ALL during 2008-2013 and treated according to the NOPHO (Nordic Society of Pediatric Hematology and Oncology)-ALL 2008 protocol. The cohort was followed until December 2014. Cox proportional regression was used to compute hazard ratios (HRs). RESULTS: TE events (n = 63) occurred most frequently in conjunction with asparaginase (ASP) administration (52/63). The cumulative incidence of TE was 6.1% (95% confidence interval [CI], 4.8-7.7). Being aged 15-17 years was associated with an increased risk of TE (adjusted HR of 4.0; 95% CI, 2.1-7.7). We found a TE-associated 30-day case fatality of 6.4% (95% CI, 1.8-15.5) and TE-related truncation of ASP therapy in 36.2% (21/58). Major hemorrhage occurred in 3.5% (2/58) of anticoagulated patients. Minor hemorrhage was reported in two out of 58 patients. No major bleeds occurred in children who received low-molecular-weight heparin. CONCLUSIONS: Methods to identify children and adolescents who will benefit from thromboprophylaxis during ALL treatment are called for. The truncation of ASP should be avoided. The long-term survival outcomes for ALL patients with TE require close monitoring in the future.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Tromboembolia/epidemiología , Adolescente , Distribución por Edad , Anticoagulantes/efectos adversos , Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Niño , Preescolar , Estonia/epidemiología , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Incidencia , Lactante , Lituania/epidemiología , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Países Escandinavos y Nórdicos/epidemiología , Tromboembolia/diagnóstico , Tromboembolia/mortalidad , Tromboembolia/prevención & control , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Leucocitosis/sangre , Leucocitosis/mortalidad , Mortalidad/tendencias , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Recuento de Leucocitos , Leucocitosis/epidemiología , Leucocitosis/etiología , Masculino , Morbilidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Pronóstico , Tasa de SupervivenciaAsunto(s)
Aberraciones Cromosómicas , Resistencia a Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Corticoesteroides/farmacología , Asparaginasa/farmacología , Niño , Preescolar , Cromosomas Humanos Par 20 , Cromosomas Humanos Par 9 , Citarabina/farmacología , Humanos , Lactante , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.
Asunto(s)
Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Reordenamiento Génico , Leucemia Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Enfermedad Aguda , Adolescente , Antineoplásicos/farmacología , Linaje de la Célula , Niño , Preescolar , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 9 , Citarabina/farmacología , Pruebas Inmunológicas de Citotoxicidad , Doxorrubicina/farmacología , Femenino , Fluorometría , Glucocorticoides/farmacología , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Recién Nacido , Leucemia Mieloide/inmunología , Masculino , Proteína de la Leucemia Mieloide-Linfoide , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Estudios Prospectivos , Estadísticas no Paramétricas , Translocación GenéticaRESUMEN
With greatly increased survival rates after childhood leukemia during the last 3 decades, the long-term effects of the treatment have become more evident. The disease and its treatment impair the immune system, but the duration of this impairment is unknown. The authors studied the serum concentrations of immunoglobulins and IgG subclasses in 20 Icelandic children cured of leukemia on average 8 years and 3 months after their treatment ended. Although no marked deviations were found in the concentrations of the main immunoglobulin classes IgA, IgM, IgG, and IgE, the IgG subclass levels were below reference values. The patients had on average 0.9 of age standardized reference values of IgG1, 0.5 of IgG2, 0.8 of IgG3, and 0.7 of IgG4. However, none had any autoimmune diseases or a markedly increased tendency for infections. The results indicate that although the immunoglobulin classes regain their normal values within a few years after cessation of treatment, recovery of the IgG subclasses, especially IgG2, is impaired.
Asunto(s)
Inmunoglobulinas/sangre , Inmunoglobulinas/clasificación , Leucemia/inmunología , Leucemia/terapia , Adolescente , Adulto , Edad de Inicio , Trasplante de Médula Ósea , Niño , Estudios de Seguimiento , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/clasificación , Inmunoglobulina E/sangre , Inmunoglobulina E/clasificación , Inmunoglobulina G/sangre , Inmunoglobulina G/clasificación , Inmunoglobulina M/sangre , Inmunoglobulina M/clasificación , Leucemia/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mieloide Aguda/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Factores de Tiempo , Irradiación Corporal TotalRESUMEN
The platelet GPIb-V-IX complex is the receptor for the initial binding of von Willebrand factor (vWF) mediating platelet adhesion. The complex is composed of four membrane-spanning glycoproteins (GP): GPIbalpha, GPIbbeta, GPIX, and GPV. Bernard-Soulier syndrome results from a qualitative or quantitative defect in one or more components of the platelet membrane GPIb-V-IX complex. We describe the molecular basis of a novel Bernard-Soulier syndrome variant in two siblings in whom GPIbalpha was not detected on the platelet surface but that was present in a soluble form in plasma. DNA sequence analysis showed that the affected individuals were compound heterozygotes for two mutations. One, inherited from a maternal allele, a T777 --> C point mutation in GPIbalpha converting Cys65 --> Arg within the second leucine rich repeat, the other, a single nucleotide substitution (G2078 --> A) for the tryptophan codon (TGG) causing a nonsense codon (TGA) at residue 498 within the transmembrane region of GPIbalpha, inherited from a mutant paternal allele. The Bernard-Soulier phenotype was observed in siblings who were compound heterozygotes for these two mutations. Although GPIbalpha was not detected on the surface of the patient's platelets, soluble GPIbalpha could be immunoprecipitated from plasma. When plasmids encoding GPIbalpha containing the Cys65 --> Arg mutation were transiently transfected into Chinese hamster ovary (CHO) cells stably expressing the GPbeta-IX complex (CHObetaIX), the expression of GPIbalpha was similar to the wild-type (WT) GPIbalpha, but did not bind vWF. When plasmids encoding GPIbalpha containing the Trp498 --> stop were transiently transfected into CHObetaIX, the surface expression of GPIbalpha was barely detectable compared with the WT GPIbalpha. Thus, this newly described compound heterozygous defect produces Bernard-Soulier syndrome by a combination of synthesis of a nonfunctional protein and of a truncated protein that fails to insert into the platelet membrane and is found circulating in plasma.
Asunto(s)
Mutación , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Adulto , Secuencia de Aminoácidos , Animales , Sitios de Unión/genética , Células CHO , Preescolar , Cricetinae , Femenino , Heterocigoto , Humanos , Ligandos , Masculino , Datos de Secuencia Molecular , Unión Proteica/genéticaRESUMEN
PURPOSE: The comparable health-care organizations and common Cancer Registry for childhood malignancies in the five Nordic countries offered an opportunity to conduct an epidemiological study on a reasonable number of childhood non-Hodgkin's lymphoma (NHL) cases collected in a population-based manner. MATERIAL AND METHODS: All childhood cases (0-14.9 years at diagnosis) reported during the 5-year period of 1985-1989 to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) Cancer Registry for childhood malignancies were reviewed and analyzed according to age, Murphy's stage, gender, site, and survival. RESULTS: The annual incidence of NHL is 0.7 per 100,000 children in the five Nordic countries, constituting 5% of all childhood malignancies. Age distribution was even; the male/female ratio was 3:1. Age and stage were shown by Cox regression analysis to be independent prognostic factors. Older age and lower stage affected outcome favorably. The stage and site distribution was similar to previous reports. Survival data were in accordance with those expected with modern treatment protocols. CONCLUSIONS: The incidence and relative frequency of NHL in childhood in the five Nordic countries is in agreement with previously reported data, but the even distribution of cases throughout childhood is a new finding. Older age at onset and stage of disease affect outcome favorably, whereas male gender contrary to acute lymphoblastic leukemia was not found to affect outcome.
Asunto(s)
Linfoma no Hodgkin/epidemiología , Adolescente , Factores de Edad , Niño , Preescolar , Dinamarca/epidemiología , Femenino , Finlandia/epidemiología , Humanos , Islandia/epidemiología , Masculino , Noruega/epidemiología , Estudios Prospectivos , Sistema de Registros , Factores Sexuales , Suecia/epidemiologíaRESUMEN
Normal and aberrant immune receptor gene assembly each produce site-specific DNA rearrangements in leukemic lymphoblasts. In either case, these rearrangements provide useful clonal markers for the leukemias in question. In the t(1;14)(p34;q11) translocation associated with T cell acute lymphoblastic leukemia (T-ALL), the breakpoints on chromosome 1 interrupt the tal-1 gene. A site-specific deletion interrupts the same gene in an additional 26% of T-ALL. Thus, nearly one-third of these leukemias contain clustered rearrangements of the tal-1 locus. To test whether these rearrangements can serve as markers for residual disease, we monitored four patients with T-ALL; three of the leukemias contained a deleted (tald) and one a translocated (talt) tal-1 allele. These alleles were recognized by a sensitive amplification/hybridization assay. tald alleles were found in the blood of one patient during the 4th mo of treatment but not thereafter. Using a quantitative assay to measure the fraction of tald alleles in DNA extracts, we estimated that this month 4 sample contained 150 tald copies per 10(6) genome copies. The patient with t(1;14)(p34;q11) (talt) leukemia developed a positive assay during the 20th mo of treatment. By standard criteria, all four patients remain in complete remission 11-20 mo into treatment. We conclude that tal-1 rearrangements provide useful clonal markers for approximately 30% of T-ALLs.
Asunto(s)
Reordenamiento Génico , Leucemia-Linfoma de Células T del Adulto/genética , Alelos , Secuencia de Bases , Médula Ósea/química , Deleción Cromosómica , Humanos , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Translocación GenéticaRESUMEN
To evaluate the clinical course and characteristics of children with chronic neutropenia, we reviewed the charts of all such patients seen at our center during a 13-year period. A total of 50 patients with chronic neutropenia were identified. Three patients had documented congenital neutropenia, and two siblings had cyclic neutropenia. The remaining 45 children had chronic neutropenia of unknown origin. All children except two had a remarkably benign course despite markedly reduced granulocyte counts. Of six girls in this group who had abscess or cellulitis of the labia majora, it was a presenting manifestation in three. Resolution of neutropenia was documented in 23 (62%) of 37 patients for whom follow-up information was available, with a median duration of neutropenia of 19 months. No differences were evident between patients with positive antineutrophil antibody test results and those in whom the test yielded negative results or was not performed. Chronic neutropenia in childhood is a relatively uncommon entity, characterized by a benign course and eventual resolution in the majority of patients.
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Neutropenia/fisiopatología , Niño , Preescolar , Enfermedad Crónica , Femenino , Humanos , Lactante , Masculino , Neutropenia/diagnóstico , Neutropenia/terapia , Pronóstico , Estudios RetrospectivosAsunto(s)
Metotrexato/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/prevención & control , Niño , Preescolar , Humanos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Inducción de RemisiónRESUMEN
To develop a sensitive and specific assay for minimal residual disease in acute lymphoblastic leukemia (ALL), we exploited the enormous diversity of genomic sequences created by immune receptor gene rearrangements. To isolate clone-specific sequences, we first synthesized oligonucleotides that match conserved variable (VH) and joining (JH) sequences flanking the third hypervariable region (HVR3) in the rearranged immunoglobulin heavy chain (IgH) locus. In polymerase chain reactions (PCR), these primers were then used to amplify the intervening HVR3 segments from leukemic DNA samples. Of 12 B-lineage ALLs studied, ten generated one or more fragments of the size expected for HVR3 gene segments. Thus, this single pair of amplimers was sufficient to isolate HVR3 sequences from a majority of acute lymphoblastic leukemias. To verify that the amplified fragments originated from HVR3 alleles and to assess their diversity, we sequenced 7 PCR products derived from 6 leukemias. In addition to elements of recognized D segments, each of the 7 fragments contained novel VH-D and D-JH junctional sequences, including N nucleotides, not known to be present in the germline. Each sequence was unique, and allele-specific oligonucleotide probes hybridized only to HVR3 segments from which the probes were derived. Therefore, as anticipated, these HVR3 segments appeared to possess the diversity required to serve as clonal markers for leukemic populations. To demonstrate that these amplified HVR3 alleles could serve as the basis for a sensitive and specific assay to detect rare leukemic cells, we analyzed in detail one pre-B leukemia that had rearranged 2 IgH alleles. The HVR3 sequences were shown to be linked to rearranged JH-containing restriction fragments in digests of genomic DNA, establishing their origin in the leukemic cells. We synthesized oligonucleotides corresponding to the unique junctional sequences in the HVR3 segments. Using these novel amplimers in an allele-specific amplification and hybridization procedure, we showed that this assay can detect 10 leukemic cells in a background of 10(6) normal blood mononuclear cells. In contrast, the leukemic HVR3 sequences were not detected in extracts of normal or unrelated remission leukemic leukocytes. We conclude that the assay for specific IgH HVR3 sequences is a realistic strategy for detection of minimal residual disease in B-lineage ALL.
Asunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Sondas de Oligonucleótidos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Alelos , Secuencia de Bases , Southern Blotting , ADN/genética , Amplificación de Genes/genética , Amplificación de Genes/inmunología , Reordenamiento Génico/genética , Reordenamiento Génico/inmunología , Humanos , Cadenas Pesadas de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/inmunología , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunologíaRESUMEN
We reviewed the records of all patients with a diagnosis of ALL made at our center during a 13-year period to determine the relationship between bone pain and the hematologic findings at diagnosis of acute lymphoblastic leukemia. Of 296 eligible patients, 179 (60%) had no bone pain (group 1), 65 (22%) had some bone pain (group 2), and 52 (18%) had prominent bone pain that overshadowed other manifestations of the leukemia (group 3). Statistically significant differences were found between the groups for hemoglobin concentration (p less than 0.001), leukocyte count (p = 0.014), absolute neutrophil count (p = 0.002), percentage of circulating blast cells (p = 0.009), and platelet count (p less than 0.001). Children in group 3 had values closer to normal for all these values than those of patients in the other groups. Group 3 patients had symptoms an average of more than 2 weeks longer before diagnosis, and had significantly lower serum uric acid and higher calcium levels than patients in the other groups had. No differences were detected among the groups in age at diagnosis, gender, or survival rate. We conclude that children with acute lymphoblastic leukemia who have prominent bone pain preceding the diagnosis frequently have nearly normal hematologic values and that this feature may contribute to a delay in diagnosis.
Asunto(s)
Dolor/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Huesos , Niño , Femenino , Hemoglobinometría , Humanos , Recuento de Leucocitos , Masculino , Recuento de Plaquetas , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMEN
We describe a 10-year-old girl, who presented with thrombotic thrombocytopenic purpura (TTP) and shortly thereafter developed systemic lupus erythematosus (SLE). The association between TTP and SLE is known, but this is the first report of SLE presenting as TTP.